Cholangitis, SclerosingPhase 1NCT01456468
Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis
A Phase 1 study testing Oral all-trans retinoic acid (ATRA) in people with Cholangitis, Sclerosing, run by Yale University at 2 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Cholangitis, Sclerosing
- What is being tested?
- Oral all-trans retinoic acid (ATRA)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 2 sitesUnited States
- Study dates
- Oct 2011to Dec 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Yale University School of Medicine - 333 Cedar St - 1080 LMP
New Haven, Connecticut, 06520
Mayo Clinic
Rochester, Minnesota, 55905
About this study
Official title: Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis - A Human Pilot Study
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%.
Read the 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.
- Conditions
- Cholangitis, Sclerosing
- Being tested
- Oral all-trans retinoic acid (ATRA)
- Keywords
- Cholangitis, Sclerosing, Tretinoin, Ursodeoxycholic Acid
- Medical subject headings
- Cholangitis, Sclerosing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral all-trans retinoic acid (ATRA)Drug
Also called The medication is 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.
| Study group | Role | What they receive |
|---|---|---|
| UDCA + ATRA | Experimental | This is a single-arm study. All subjects will take UDCA and ATRA. Receives: Drug: Oral all-trans retinoic acid (ATRA) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and after 3 months of treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Oct 2011 (estimated)
- Study startOct 2011
- Primary completionJun 2014
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cholangitis, SclerosingStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Mayo Clinic
- Responsible party
- Principal investigator, James Boyer, Yale University
- Investigators
- James L Boyer, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01456468
- Sponsor's protocol ID
- 1012007734
- Status last verified
- Jul 2016
- First submitted
- 14 Oct 2011
- Last updated
- 14 Jul 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 21274875
Study at a glance
From the registry record, last updated by the sponsor on 14 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combination Therapy With Ursodeoxycholic Acid (UDCA) and All-Trans Retinoic Acid (ATRA) for Treatment of Primary Sclerosing Cholangitis - A Human Pilot Study
- ClinicalTrials.gov ID
- NCT01456468
- Acronym / sponsor ID
- 1012007734
- Conditions
- Cholangitis, Sclerosing
- Keywords
- Cholangitis, Sclerosing, Tretinoin, Ursodeoxycholic Acid
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Mayo Clinic
- Study start
- Oct 2011
- Primary completion
- Jun 2014 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 20 Oct 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| UDCA + ATRA | Experimental | Drug: Oral all-trans retinoic acid (ATRA)This is a single-arm study. All subjects will take UDCA and ATRA. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
- Age between 18 and 80.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral all-trans retinoic acid (ATRA)Also: The medication is 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. | Drug | UDCA + ATRA |
Primary outcome
Improvement in serum alkaline phosphatase levels
Time frame: Baseline and after 3 months of treatment.
The primary outcome measure is a 30% improvement in serum alkaline phosphatase in subjects, comparing pre- and post-treatment values for each individual.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jul 2016.
- Background: PubMed 21274875He 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James L Boyer, MD principal investigator
Yale University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Oral all-trans retinoic acid (ATRA) in people with Cholangitis, Sclerosing, run by Yale University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement in serum alkaline phosphatase levels (time frame: Baseline and after 3 months of treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01456468, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2016.