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A Study Of Ursolic Acid For Primary Sclerosing Cholangitis

Primary Purpose

Primary Sclerosing Cholangitis

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Ursolic acid

About this trial

This is an interventional treatment trial for Primary Sclerosing Cholangitis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Univeristy of California Davis Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Healthy Controls

PSC Single Dose

PSC Multiple Dose

Arm Description

Healthy subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg

PSC subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg

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

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Number of serious adverse events or Grade 3-4 biochemical abnormalities

Secondary Outcome Measures

maximum plasma concentration (C¬max)

Measured in mass of drug/ volume of fluid, The peak plasma concentration of a drug after administration.

half-life (t1/2),

measured in time ,Time to reach Cmax.

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).

clearance

Measured in Volume/ time, The volume of plasma cleared of the drug per unit time

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).

Alanine aminotransferase (ALT)

Change in ALT from baseline to 24 weeks

Total bilirubin

Change in total bilirubin from baseline to 24 weeks.

C-reactive Protein (CRP)

Change in CRP from baseline to 24 weeks.

Mayo Risk Score (MRS)

Change in MRS from baseline to 24 weeks.

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.

Full Information

NCT ID

NCT03216876

First Posted

January 5, 2016

Last Updated

July 21, 2017

Sponsor

University of California, Davis

1. Study Identification

Unique Protocol Identification Number

NCT03216876

Brief Title

A Study Of Ursolic Acid For Primary Sclerosing Cholangitis

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Withdrawn

Why Stopped

Lack of feasibility

Study Start Date

September 2017 (Anticipated)

Primary Completion Date

January 2019 (Anticipated)

Study Completion Date

July 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of California, Davis

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Sclerosing Cholangitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Healthy Controls

Arm Type

Experimental

Arm Description

Healthy subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg

Arm Title

PSC Single Dose

Arm Type

Experimental

Arm Description

PSC subjects will assigned to ursolic acid taken orally as a single dose of 40 mg, 80 mg, and 120 mg

Arm Title

PSC Multiple Dose

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ursolic acid

Other Intervention Name(s)

urson, prunol, malol, 3-beta-3-hydroxy-urs-12-ene-28-oic-acid

Intervention Description

Ursolic acid (UA) is a natural triterpenoid carboxylic acid, which has been studied for its anti-proliferative and anti-inflammatory activities.

Primary Outcome Measure Information:

Title

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Description

Number of serious adverse events or Grade 3-4 biochemical abnormalities

Time Frame

24 hours

Secondary Outcome Measure Information:

Title

maximum plasma concentration (C¬max)

Description

Measured in mass of drug/ volume of fluid, The peak plasma concentration of a drug after administration.

Time Frame

24 hours

Title

half-life (t1/2),

Description

measured in time ,Time to reach Cmax.

Time Frame

24 hours

Title

volume of distribution (Vd)

Description

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).

Time Frame

24 hours

Title

clearance

Description

Measured in Volume/ time, The volume of plasma cleared of the drug per unit time

Time Frame

24 hours

Title

Area under the concentration-time curve (AUC)

Description

Measured in mass/(volume*time), The integral of the concentration-time curve (after a single dose or in steady state).

Time Frame

24 hours

Title

Alanine aminotransferase (ALT)

Description

Change in ALT from baseline to 24 weeks

Time Frame

24 weeks

Title

Total bilirubin

Description

Change in total bilirubin from baseline to 24 weeks.

Time Frame

24 weks

Title

C-reactive Protein (CRP)

Description

Change in CRP from baseline to 24 weeks.

Time Frame

24 weks

Title

Mayo Risk Score (MRS)

Description

Change in MRS from baseline to 24 weeks.

Time Frame

24 weks

Title

Biochemical response

Description

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.

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christopher Bowlus, MD

Organizational Affiliation

University of California, Davis

Official's Role

Principal Investigator

Facility Information:

Facility Name

Univeristy of California Davis Medical Center

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

12. IPD Sharing Statement

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