Pentoxifylline for Primary Biliary Cirrhosis

A Pilot Study of Pentoxifylline for the Treatment of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is cholestatic liver disease characterized by progressive destruction of small bile ducts within the liver that can lead to end stage liver disease and all its complications.

Although ursodeoxycholic acid (UDCA) is associated with increased survival in many patients with PBC, there is absence of an adequate response to UDCA in a significant proportion of PBC patients.

Tumor necrosis factor alpha (TNF-alpha) is a cytokine that plays an important role in the pathogenesis of PBC. Other fibrosis biomarkers such as tissue metallo proteinase 1 (TIMP-1) are associated with progression of liver fibrosis in PBC. Pentoxifylline (PTX) is a methylxanthine derivative that inhibits pro-inflammatory cytokines and also has shown anti-fibrotic effects in serum of patients with PBC. Furthermore, PTX has well known clinical and safety profiles. The main hypothesis of this study is that therapy with pentoxifylline (PTX) will result in improvement of liver disease in PBC patients who are incomplete responders to UDCA.

The focus of this proposal is on the effectiveness of PTX in improving laboratory parameters of liver disease and levels of cytokines involved in the pathogenesis of the disease in patients with PBC.

Study Overview

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

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

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients ages 18 to 76 years.

• Established diagnosis of PBC based on at least three of the following criteria:

  • Detectable anti-mitochondrial antibodies (AMA)
  • Cholestatic biochemical pattern
  • Liver biopsy compatible with PBC
  • Appropriate exclusion of other liver diseases.
• Therapy with UDCA at adequate dose (13-15mg/kg/d) for at least six months and evidence of suboptimal response defined by alkaline phosphatase levels that did not normalize and remain elevated by at least 1.5 times the upper limit of normal.
• No history or present hepatic decompensation (e.g. variceal hemorrhage, encephalopathy, or poorly controlled ascites).

Exclusion Criteria:

• Findings highly suggestive of liver disease of other etiology.
• A score >=10 points on the Revised Scoring System for autoimmune hepatitis (AIH), supporting a diagnosis of PBC/AIH overlap.
• Patients on steroids (systemic), immunosuppressants, or immunomodulatory agents within the previous 6 months.
• Patients with clinical or laboratory evidence suggestive of decompensated cirrhosis.
• Hypersensitivity to PTX or the methylxanthines (caffeine, theophylline, theobromine).
• History of cerebral or retinal hemorrhage.
• Other medical comorbidities (such as cardiac, renal, cancer) that would interfere with completion of the study.
• Patients taking Theophylline or Coumadin because of potential drug-drug interactions with PTX. In addition, patients taking low molecular weight heparin preparations.
• Pregnant or nursing women.

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: Pentoxifylline 400 mg TID; This study is an open label pilot with only one arm.	Drug: Pentoxifylline; Patients will take 400mg of pentoxifylline three times daily for a total duration of 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Alkaline Phosphatase Levels.	Serum alkaline phosphatase levels at entry and at 6 months of therapy with PTX will be measured and compared.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Concentration of Tissue Inhibitor Metalloproteinase 1 (TIMP-1) After PTX Therapy.	Serum concentration of tissue inhibitor metalloproteinase 1 (TIMP-1), a fibrosis biomarker of interest, will be measured and the change in serum levels between entry and end of study will be calculated.	6 months
Safety of Therapy in the Pilot Study of PTX Therapy in Patients With PBC Will be Assessed	The number of participants that experienced any severe adverse events will be monitored and recorded.	6 months

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Claudia O. Zein, MD, MSc, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: November 24, 2010
• First Submitted That Met QC Criteria: November 26, 2010
• First Posted (Estimate): November 29, 2010

Study Record Updates

• Last Update Posted (Estimate): December 9, 2013
• Last Update Submitted That Met QC Criteria: October 16, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: 07-1003