Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis
Primary Purpose
Cholangitis, Sclerosing
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Oral all-trans retinoic acid (ATRA)
Sponsored by
About this trial
This is an interventional treatment trial for Cholangitis, Sclerosing focused on measuring Cholangitis, Sclerosing, Tretinoin, Ursodeoxycholic Acid
Eligibility 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:
- Cholangitis within the past 12 months.
- Presence or progression of biliary abnormalities on MRI/MRC.
- 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.
Sites / Locations
- Yale University School of Medicine - 333 Cedar St - 1080 LMP
- Mayo Clinic
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
UDCA + ATRA
Arm Description
This is a single-arm study. All subjects will take UDCA and ATRA.
Outcomes
Primary Outcome Measures
Improvement in serum alkaline phosphatase levels
The primary outcome measure is a 30% improvement in serum alkaline phosphatase in subjects, comparing pre- and post-treatment values for each individual.
Secondary Outcome Measures
Full Information
NCT ID
NCT01456468
First Posted
October 14, 2011
Last Updated
July 12, 2016
Sponsor
Yale University
Collaborators
Mayo Clinic
1. Study Identification
Unique Protocol Identification Number
NCT01456468
Brief Title
Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis
Official Title
Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis - A Human Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
December 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Yale University
Collaborators
Mayo Clinic
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cholangitis, Sclerosing
Keywords
Cholangitis, Sclerosing, Tretinoin, Ursodeoxycholic Acid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)
8. Arms, Groups, and Interventions
Arm Title
UDCA + ATRA
Arm Type
Experimental
Arm Description
This is a single-arm study. All subjects will take UDCA and ATRA.
Intervention Type
Drug
Intervention Name(s)
Oral all-trans retinoic acid (ATRA)
Other Intervention Name(s)
The medication is all-trans retinoic acid (ATRA).
Intervention Description
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.
Primary Outcome Measure Information:
Title
Improvement in serum alkaline phosphatase levels
Description
The primary outcome measure is a 30% improvement in serum alkaline phosphatase in subjects, comparing pre- and post-treatment values for each individual.
Time Frame
Baseline and after 3 months of treatment.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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:
Cholangitis within the past 12 months.
Presence or progression of biliary abnormalities on MRI/MRC.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James L Boyer, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University School of Medicine - 333 Cedar St - 1080 LMP
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
21274875
Citation
He H, Mennone A, Boyer JL, Cai SY. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology. 2011 Feb;53(2):548-57. doi: 10.1002/hep.24047. Epub 2010 Dec 10.
Results Reference
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Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis
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