An Efficacy Trial of Low Dose All-trans Retinoic Acid in Patients With Primary Sclerosing Cholangitis

• Sponsor: Yale University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03359174
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Actual Duration (Months): 31.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine whether a low dose of ATRA will improve laboratory tests of liver and bile duct inflammation in patients with PSC. The investigators will also look for changes to other blood tests which are related to inflammation, scarring, and the immune system.

Condition or Disease	Intervention/Treatment	Phase
Cholangitis, Sclerosing	Drug: All-trans retinoic acid	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Efficacy Trial of Low Dose All-trans Retinoic Acid (ATRA) in Patients With Primary Sclerosing Cholangitis
• Actual Study Start Date: May 29, 2018
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Jan 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All-trans retinoic acid (ATRA) therapy Fixed low dose of ATRA 10 mg twice daily for 24 weeks.	Drug: All-trans retinoic acid; Fixed low dose of ATRA 10 mg twice daily for 24 weeks.

Outcome Measures

Primary Outcome Measures

1. Change of Serum Alkaline Phosphatase (ALP) [Baseline to week 24.]

   Blood will be drawn at each time point to compare pre- and post-treatment values for each individual.

Secondary Outcome Measures

1. Change in Patients Who Have Normalization of Serum ALP or Reduction to Less Than 1.5 x Upper Limit of Normal (ULN) [Baseline to week 24.]

   Blood is drawn at each time point to assess the outcome.

2. The Percent of Patients Who Have Reduction of Serum C4 by 50% [Baseline to week 24.]

   Blood is drawn at each time point to assess the outcome.

3. The Percent of Patients Who Have Reduction of Serum Bile Acids by 50% [Baseline to week 24.]

   Blood is drawn at each time point to assess the outcome.

4. The Percent of Patients Who Have Reduction of Serum Alanine Aminotransferase (ALT) by 50% [Baseline to week 24.]

   Blood is drawn at each time point to assess the outcome.

5. The Percent of Patients Who Have Reduction of Serum Enhanced Liver Fibrosis Score (ELF) by 10% [Baseline to week 24.]

   Blood is drawn at each time point to assess the outcome.

6. The Percent of Patients Who Have Improvement in Fibrosis Per Transient Elastography by at Least 1 Stage [Baseline to week 24.]

   Transient Elastography will be performed at baseline and week 24 to assess the outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males and females ages 18-80

• Diagnosis of large-duct PSC based on ERCP or MRCP, or liver biopsy findings without alternative explanation for findings, for at least 6 months.

• Serum ALP levels persistently more than 1.5 x upper limit of normal over the past 6 months.

• Ursodeoxycholic acid therapy must be discontinued for at least 3 months.

• At least 2 forms of barrier protection for males and females of child-bearing age.

Exclusion Criteria:

• Small duct PSC, overlap with autoimmune hepatitis, IgG4 disease or secondary sclerosing cholangitis.

• Any malignancy, presently or within the past 5 years, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix or in situ prostate cancer.

• Viral hepatitis including hepatitis A, B, C, D, E.

• Decompensated cirrhosis, or planned liver transplantation.

• Recent diagnostic or therapeutic biliary manipulation (endoscopic, radiologic) within the past 3 months.

• Ascending Cholangitis requiring antibiotics within the past 3 months.

• Uncontrolled IBD, or IBD requiring the use of steroids.

• Acute or Chronic Kidney Disease with serum creatinine > 2 mg/dL.

• Allergy to ATRA or vitamin A compounds.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States	06510

Sponsors and Collaborators

• Yale University

Investigators

• Principal Investigator: James Boyer, MD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 17, 2018

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT03359174
• Other Study ID Numbers: 2000021447
• First Posted: Dec 2, 2017
• Last Update Posted: Aug 9, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cholangitis; Cholangitis, Sclerosing; Tretinoin

Study Results

Participant Flow

Recruitment Details	Patients were recruited from physicians case load at Yale University, Digestive Disease's Liver clinic between May 2018 and December 2018. Both participants were enrolled in May of 2018.
Pre-assignment Detail	Of the two patients who screened, both met inclusion and exclusion criterial and were enrolled

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Period Title: Overall Study
STARTED	2
COMPLETED	1
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	2 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	2 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Change of Serum Alkaline Phosphatase (ALP)
Description	Blood will be drawn at each time point to compare pre- and post-treatment values for each individual.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

2. Secondary Outcome

Title	Change in Patients Who Have Normalization of Serum ALP or Reduction to Less Than 1.5 x Upper Limit of Normal (ULN)
Description	Blood is drawn at each time point to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, and no trial end point was achieved so there was no data to record. .

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

3. Secondary Outcome

Title	The Percent of Patients Who Have Reduction of Serum C4 by 50%
Description	Blood is drawn at each time point to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, data not reported.

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

4. Secondary Outcome

Title	The Percent of Patients Who Have Reduction of Serum Bile Acids by 50%
Description	Blood is drawn at each time point to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, data not reported.

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

5. Secondary Outcome

Title	The Percent of Patients Who Have Reduction of Serum Alanine Aminotransferase (ALT) by 50%
Description	Blood is drawn at each time point to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, data not reported.

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

6. Secondary Outcome

Title	The Percent of Patients Who Have Reduction of Serum Enhanced Liver Fibrosis Score (ELF) by 10%
Description	Blood is drawn at each time point to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, data not reported.

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

7. Secondary Outcome

Title	The Percent of Patients Who Have Improvement in Fibrosis Per Transient Elastography by at Least 1 Stage
Description	Transient Elastography will be performed at baseline and week 24 to assess the outcome.
Time Frame	Baseline to week 24.

Outcome Measure Data

Analysis Population Description

Only 1 patient completed the study, data not reported.

Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
Measure Participants	0

Adverse Events

Time Frame	Up to 28 weeks post treatment initiation.
Arm/Group Title	All-trans Retinoic Acid (ATRA) Therapy
Arm/Group Description	Fixed low dose of ATRA 10 mg twice daily for 24 weeks. All-trans retinoic acid: Fixed low dose of ATRA 10 mg twice daily for 24 weeks.
All Cause Mortality
	All-trans Retinoic Acid (ATRA) Therapy
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Serious Adverse Events
	All-trans Retinoic Acid (ATRA) Therapy
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Other (Not Including Serious) Adverse Events
	All-trans Retinoic Acid (ATRA) Therapy
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Hepatobiliary disorders
alkaline phosphatase increase	1/2 (50%)	1
Blood bilirubin increased	1/2 (50%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.