Moexipril for Primary Biliary Cirrhosis

Open-Label Pilot Investigation of Moexipril for the Treatment of Primary Biliary Cirrhosis (PBC)

The blockade of angiotensin II synthesis attenuates hepatic fibrosis in different experimental models of chronic liver injury. We aimed to determine the safety and efficacy of moexipril, an angiotensin-converting enzyme (ACE) inhibitor, on liver biochemistries, Mayo risk score, and health-related quality of life in patients with primary biliary cirrhosis (PBC) who have had a suboptimal response to ursodeoxycholic acid (UDCA).

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Drug: Moexipril

Detailed Description

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune cause characterized by progressive inflammatory destruction of interlobular and septal bile ducts, resulting in fibrosis and eventual cirrhosis (1). In PBC patients, the most disabling symptoms are fatigue and pruritus which diminish health-related quality of life (HRQL. Ursodeoxycholic acid (UDCA), at a dose of 13 to 15 mg/kg per day, is a safe and effective medical therapy for most patients with PBC. Nevertheless, UDCA therapy has not ameliorated symptoms associated with PBC. Some UDCA-treated patients show progressive disease resulting in the liver transplantation or death from liver-related causes. For these patients, who show a persistent elevation of serum alkaline phosphatase at least twice the normal level after 6 months of UDCA monotherapy (incomplete responders), the evaluation of combination therapy in clinical trials has been recommended.

Moexipril is a long-acting, nonsulfhydryl ACE inhibitor with lipophilicity, and so can readily penetrate lipid membranes and thus target tissue ACE in addition to plasma ACE. This drug also demonstrated antioxidative properties in addition to efficiently controlling blood pressure in hypertensive postmenopausal subjects. Moreover, quality-of-life data suggest favorable effects of moexipril treatment in a patient population at high cardiovascular risk. The tolerability and safety profile of moexipril resembles that of other ACE inhibitors along with no reports of hepatotoxicity in controlled trials. Hence, moexipril is an attractive drug for evaluation in patients with chronic liver disease.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• PBC patients treated with UDCA (daily dose of 13 to 15 mg/kg for at least 6 months) and an incomplete response defined by persistent elevation of serum alkaline phosphatase activity at least 2 times the upper limit of normal

Exclusion Criteria:

• age less than 18 years
• pregnancy or nursing
• anticipated need for liver transplantation within 1 year with less than a 80% one-year survival determined by the Mayo risk score
• complications of cirrhosis such as recurrent variceal hemorrhage, portosystemic encephalopathy, and refractory ascites
• history of coexistent severe cardiovascular disease including aortic stenosis
• history of coexistent severe renal disease (defined as elevation of serum creatinine more than 1.5 mg/dL) including renal artery stenosis
• history of allergy to ACE inhibitors
• current use of an ACE inhibitors or AT1 receptor antagonists in the past 3 months
• previous treatment with immunosuppressive agents or any experimental drug in the preceding 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: A, 1; All patients received an open-label moexipril during the study period.

Drug: Moexipril; Moexipril was given at a starting dose of 7.5 mg daily for 1 week to all enrolled patients. If tolerated (no clinically significant hypotension or medication associated adverse event), the daily dosage was increased to 15 mg daily at the beginning of the 2nd treatment week. Patients took moexipril orally in the morning and 1 hour prior to food intake. The target dose was maintained for the 1-year period of the study unless the development of toxicities warranted dose reduction or discontinuation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
change in liver biochemistries and Mayo risk score for PBC	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
change in health-related quality of life in PBC	12 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: UCB Pharma
• Investigators: Principal Investigator: Keith D Lindor, MD, Mayo Clinic and Foundation

Publications and helpful links

General Publications

• Talwalkar JA, Lindor KD. Primary biliary cirrhosis. Lancet. 2003 Jul 5;362(9377):53-61. doi: 10.1016/S0140-6736(03)13808-1.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (Actual): June 1, 2007
• Study Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: December 22, 2007
• First Submitted That Met QC Criteria: December 22, 2007
• First Posted (Estimate): January 8, 2008

Study Record Updates

• Last Update Posted (Estimate): May 23, 2011
• Last Update Submitted That Met QC Criteria: May 20, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: ursodeoxycholic acid; primary biliary cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Moexipril
• Other Study ID Numbers: 1032-03