Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Mayo Clinic
Information provided by (Responsible Party):
James Boyer, Yale University
ClinicalTrials.gov Identifier:
NCT01456468
First received: October 14, 2011
Last updated: June 2, 2014
Last verified: June 2014
  Purpose

The purpose of this research study is to determine whether the combination of UDCA and ATRA taken for 3 months will improve laboratory tests of liver and bile duct inflammation in patients with Primary Sclerosing Cholangitis (PSC). Our hypothesis is that a combination of these medications will improve the liver inflammatory tests in these patients, specifically a reduction in alkaline phosphatase (AP) by at least 30%.


Condition Intervention Phase
Cholangitis, Sclerosing
Drug: Oral all-trans retinoic acid (ATRA)
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis - A Human Pilot Study

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • Improvement in serum alkaline phosphatase levels [ Time Frame: Baseline and after 3 months of treatment. ] [ Designated as safety issue: No ]
    The primary outcome measure is a 30% improvement in serum alkaline phosphatase in subjects, comparing pre- and post-treatment values for each individual.


Estimated Enrollment: 30
Study Start Date: October 2011
Estimated Study Completion Date: December 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: UDCA + ATRA
This is a single-arm study. All subjects will take UDCA and ATRA.
Drug: Oral all-trans retinoic acid (ATRA)

The subjects will continue to take their current dose of UDCA (15 mg/kg/day), as per ongoing clinical care, and need to be on a stable dose of UDCA for at least six months prior to enrollment.

The specific intervention is the addition of daily oral ATRA (45 mg/m^2) divided into 2 doses. To increase adherence to the dosing regimen, the drug will be compounded by the Research Pharmacies of Yale and Mayo into 2 formulations (30 mg and 40 mg capsules), and an Investigational New Drug (IND) permit was obtained for this process.

Other Name: The medication is all-trans retinoic acid (ATRA).

Detailed Description:

Patients with PSC often have ongoing inflammation and fibrosis (scars) along the length of their bile ducts, and eventually this involves the liver itself which can lead to cirrhosis (severe scarring), severe infections (cholangitis), bile duct cancer and death.

Although many patients are treated with UDCA, and experience improvement in their liver tests and relief of symptoms, no medical treatment to date has been found to produce a long-term improvement of inflammation and scarring, or to improved survival. For this reason, there is a great need to identify new medications which are effective for the treatment of PSC.

Recent work in animals by the research group at Yale University School of Medicine has shown that the combination of UDCA and ATRA produced a significant improvement in liver scarring and inflammation in animals with bile duct disease similar to that seen in PSC. This improvement included a lowering in the levels of bile acids, which are harmful to the liver, and a lowering of inflammation in the liver tissue of these animals. The benefits seen in this study were greater in animals receiving the combination of UDCA and ATRA compared to animals who received either medicine alone.

The medication ATRA is related to vitamin A, and has been used for many years as a topical medication in the treatment of skin conditions such as acne and psoriasis. It has also been used for nearly 20 years as an oral medicine in the treatment of a form of blood cancer (acute promyelocytic leukemia), where it is given for 90 days at a time. ATRA has been shown to produce a remission from the leukemia and is currently a standard treatment for patients with that specific condition. ATRA is not used routinely in the care of patients with liver or bile duct disease.

Based on the benefits observed by treatment with ATRA and UDCA in our animal studies, the investigators plan to study this combination in patients with PSC and believe that this may be an effective regimen for patients with this condition. The investigators will check blood tests of the liver and bile ducts before, during, and after the treatment in order to look for changes to liver tests which would be due to the medication combination.

Therefore, the goal of this study is to study the changes to liver tests in patients with PSC who take a combination of UDCA and ATRA for 90 days, comparing levels at the beginning of the study to those at the end of the study.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of PSC for at least 6 months, made by clinical evaluation in addition to one of the following: a prior endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC, also termed MRI/MRCP) or liver biopsy.
  • Progressing disease or stable disease with persistent elevation in AP despite treatment with UDCA (15 mg/kg/day) for at least 6 months.

    • Measures of progressing disease:

      1. Cholangitis within the past 12 months.
      2. Presence or progression of biliary abnormalities on MRI/MRC.
      3. Elevated liver tests (alkaline phosphatase, bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT]).
  • Age between 18 and 80.

Exclusion Criteria:

  • Pregnancy or planned pregnancy during study period and within 6 months of study completion.
  • Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher cardiac disease, hyperlipidemia, hypertriglyceridemia, hepatic injury, or adverse event related to administration of UDCA or ATRA.
  • Prior intolerance to UDCA or ATRA (or related oral vitamin A compounds).
  • Evidence of decompensated cirrhosis within the past 6 months (i.e. variceal bleeding, uncontrolled ascites, hepatic encephalopathy, jaundice).
  • Estimated need for liver transplantation within 1 year.
  • Any evidence of hepatocellular carcinoma, cholangiocarcinoma, or other malignancy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01456468

Locations
United States, Connecticut
Yale University School of Medicine - 333 Cedar St - 1080 LMP
New Haven, Connecticut, United States, 06520
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Yale University
Mayo Clinic
Investigators
Principal Investigator: James L Boyer, MD Yale University
  More Information

Publications:
Responsible Party: James Boyer, Professor of Medicine, Yale University
ClinicalTrials.gov Identifier: NCT01456468     History of Changes
Other Study ID Numbers: 1012007734
Study First Received: October 14, 2011
Last Updated: June 2, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Yale University:
Cholangitis, Sclerosing
Tretinoin
Ursodeoxycholic Acid

Additional relevant MeSH terms:
Cholangitis
Cholangitis, Sclerosing
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Tretinoin
Ursodeoxycholic Acid
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Keratolytic Agents
Dermatologic Agents
Cholagogues and Choleretics
Gastrointestinal Agents

ClinicalTrials.gov processed this record on July 24, 2014