A Study Of Ursolic Acid For Primary Sclerosing Cholangitis

Study Overview
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Brief Summary
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This is an open-label, active treatment trial to determine the pharmacokinetics of orally administered ursolic acid and to assess the potential efficacy and safety of ursolic acid in subjects with primary sclerosing cholangitis (PSC).

Detailed Description
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In the first phase of this trial, 6 healthy subjects and 2 PSC subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg to determine the optimal dose in humans. The second phase of this trial will involve 20 PSC subjects assigned to treatment with daily oral ursolic acid at the dose determined to be optimal in the first phase of the study. The treatment will last for 24 weeks with an off-treatment follow up of 28 weeks.

Official Title
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An Open-Label Study Of Ursolic Acid For Primary Sclerosing Cholangitis

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: Ursolic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 18 - 70 years of age PSC documented by typically cholangiogram findings of strictures and dilations with no evidence of a secondary cause of sclerosing cholangitis Serum alkaline phosphatase greater than 1.5 times the upper limit of the normal reference range at the UC Davis Health Systems Clinical Laboratory AST and ALT ≤ 10 x ULN Serum creatinine < 2.0 mg/dL Mayo Activity Index of < 2 (in those with ulcerative colitis or Crohn's colitis) Negative serum pregnancy test for female subjects of childbearing potential, agreement to use a highly effective method of contraception during heterosexual intercourse (females of childbearing potential), lactating females must agree to discontinue nursing before starting study treatment, and barrier contraception during heterosexual intercourse (males not vasectomized). Exclusion Criteria: Pregnancy Hepatic decompensation defined as ascites (or use of diuretics), episodes of hepatic encephalopathy, variceal bleeding or an INR > 1.2 Positive HCV RNA or HBsAg, positive anti-mitochondrial antibody, alcohol consumption greater than 21oz/week for males or 14oz/week for females Clinically significant cardiac disease, history of cholangiocarcinoma, history of liver transplantation, history of cancers, other than non-melanomatous skin cancer, within 5 years prior to screening Ascending cholangitis within 60 days of screening Use of immunosuppressants including 6-mercaptopurine, azathioprine, methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and anti-TNF or other biologics within 6 months of enrollment Use of antibiotics including vancomycin, metronidazole, or rifaximin within 60 days of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Controls<br>Healthy subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg | Drug: Ursolic acid<br>* Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.<br>* Other names: 3-beta-3-hydroxy-urs-12-ene-28-oic-acid;|
| Experimental: PSC Single Dose<br>PSC subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg | Drug: Ursolic acid<br>* Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.<br>* Other names: 3-beta-3-hydroxy-urs-12-ene-28-oic-acid;|
| Experimental: PSC Multiple Dose<br>PSC subjects assigned to treatment with daily oral ursolic acid at the dose determined to be optimal in the first phase of the study. The treatment will last for 24 weeks with an off-treatment follow up of 28 weeks | Drug: Ursolic acid<br>* Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.<br>* Other names: 3-beta-3-hydroxy-urs-12-ene-28-oic-acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Number of serious adverse events or Grade 3-4 biochemical abnormalities | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum plasma concentration (C¬max) | Measured in mass of drug/ volume of fluid, The peak plasma concentration of a drug after administration. | 24 hours | 
| half-life (t1/2), | measured in time ,Time to reach Cmax. | 24 hours | 
| volume of distribution (Vd) | Measured in volume, The apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration to drug amount in the body). | 24 hours | 
| clearance | Measured in Volume/ time, The volume of plasma cleared of the drug per unit time | 24 hours | 
| Area under the concentration-time curve (AUC) | Measured in mass/(volume*time), The integral of the concentration-time curve (after a single dose or in steady state). | 24 hours | 
| Alanine aminotransferase (ALT) | Change in ALT from baseline to 24 weeks | 24 weeks | 
| Total bilirubin | Change in total bilirubin from baseline to 24 weeks. | 24 weks | 
| C-reactive Protein (CRP) | Change in CRP from baseline to 24 weeks. | 24 weks | 
| Mayo Risk Score (MRS) | Change in MRS from baseline to 24 weeks. | 24 weks | 
| Biochemical response | Reduction in serum alkaline phosphatase by 50% or to within the normal reference range and change in alkaline phosphatase from day 0 to week 24. | 24 weeks |