Pentoxifylline for Primary Biliary Cirrhosis

• ClinicalTrials.gov Identifier: NCT01249092
• Recruitment Status: Completed
• First Posted: November 29, 2010
• Results First Posted: December 9, 2013
• Last Update Posted: December 9, 2013
• Sponsor: The Cleveland Clinic
• Information provided by (Responsible Party): Claudia Zein, MD, The Cleveland Clinic

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Primary Biliary Cirrhosis	Drug: Pentoxifylline	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Pentoxifylline for the Treatment of Primary Biliary Cirrhosis
• Study Start Date: November 2010
• Actual Primary Completion Date: June 2012
• Actual Study Completion Date: March 2013

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Change in Serum Alkaline Phosphatase Levels. [ Time Frame: 6 months ]
   Serum alkaline phosphatase levels at entry and at 6 months of therapy with PTX will be measured and compared.

Secondary Outcome Measures :

1. Change in Serum Concentration of Tissue Inhibitor Metalloproteinase 1 (TIMP-1) After PTX Therapy. [ Time Frame: 6 months ]
   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.
2. Safety of Therapy in the Pilot Study of PTX Therapy in Patients With PBC Will be Assessed [ Time Frame: 6 months ]
   The number of participants that experienced any severe adverse events will be monitored and recorded.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

The Cleveland Clinic

Investigators

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

More Information

• Responsible Party: Claudia Zein, MD, Staff Physician, Digestive Disease Institute, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01249092 History of Changes
• Other Study ID Numbers: 07-1003
• First Posted: November 29, 2010
• Results First Posted: December 9, 2013
• Last Update Posted: December 9, 2013
• Last Verified: October 2013

Keywords provided by Claudia Zein, MD, The Cleveland Clinic:

biliary cirrhosis

Additional relevant MeSH terms:

Liver Cirrhosis; Liver Cirrhosis, Biliary; Fibrosis; Pathologic Processes; Liver Diseases; Digestive System Diseases; Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Pentoxifylline; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Radiation-Protective Agents; Protective Agents; Physiological Effects of Drugs; Vasodilator Agents; Free Radical Scavengers; Antioxidants