Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis
Condition: Cholangitis, Sclerosing
MeSH terms: Cholangitis; Cholangitis, Sclerosing
Study type: Interventional
Phase: Phase 1

Summary: 
      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%.
    

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.
    

Intervention name(s): Oral all-trans retinoic acid (ATRA)
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): The medication is all-trans retinoic acid (ATRA).
Intervention MeSH terms: Tretinoin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cholangitis, Sclerosing; Tretinoin; Ursodeoxycholic Acid