A Study Of Ursolic Acid For Primary Sclerosing Cholangitis

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Primary Sclerosing Cholangitis
• Intervention / Treatment: Drug: Ursolic acid

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • Univeristy of California Davis Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Controls; Healthy subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg	Drug: Ursolic acid; Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.; Other Names: urson; prunol; malol; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid
Experimental: PSC Single Dose; PSC subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg	Drug: Ursolic acid; Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.; Other Names: urson; prunol; malol; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid
Experimental: PSC Multiple Dose; 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; Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.; Other Names: urson; prunol; malol; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, Davis
• Investigators: Principal Investigator: Christopher Bowlus, MD, University of California, Davis

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2017
• Primary Completion (Anticipated): January 1, 2019
• Study Completion (Anticipated): July 1, 2019

Study Registration Dates

• First Submitted: January 5, 2016
• First Submitted That Met QC Criteria: July 12, 2017
• First Posted (Actual): July 13, 2017

Study Record Updates

• Last Update Posted (Actual): July 25, 2017
• Last Update Submitted That Met QC Criteria: July 21, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholangitis; Cholangitis, Sclerosing; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Ursolic acid
• Other Study ID Numbers: PSC-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No