Primary Biliary Cirrhosis
Conditions
Keywords
biliary cirrhosis
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.
Interventions
DRUGPentoxifylline
Patients will take 400mg of pentoxifylline three times daily for a total duration of 6 months.
Sponsors
The Cleveland Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Alkaline Phosphatase Levels. | 6 months | Serum alkaline phosphatase levels at entry and at 6 months of therapy with PTX will be measured and compared. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Concentration of Tissue Inhibitor Metalloproteinase 1 (TIMP-1) After PTX Therapy. | 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. |
| Safety of Therapy in the Pilot Study of PTX Therapy in Patients With PBC Will be Assessed | 6 months | The number of participants that experienced any severe adverse events will be monitored and recorded. |
Countries
United States
Participant flow
Recruitment details
Patient enrollment was initiated in December 2010 and a total of 20 patients were enrolled. The last patient to complete the pilot study completed participation in June 2012.
Pre-assignment details
This was a single arm open label pilot study where all subjects received the same intervention throughout the study duration. There were no different study groups and no randomization was involved.
Participants by arm
| Arm | Count |
|---|---|
| Pentoxifylline 400 mg/d All patients received same intervention. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Expected side effect of nausea/dyspepsia | 1 |
| Overall Study | Unable to tolerate expected SE -nausea | 1 |
Baseline characteristics
| Characteristic | Pentoxifylline 400 mg/d |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age Continuous | 57.7 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Change in Alkaline Phosphatase After Pentoxifylline Therapy | Change in Serum Alkaline Phosphatase Levels. | -57.3 U/L | Standard Deviation 62.1 |
Comparison: A p-value \< 0.05 was considered statistically significant and all analyses were carried out using SAS version 9.2 (The SAS Institute, Cary, NC). Matched pairs t-test was used to compare the change in alkaline phosphatase from baseline. The efficacy of therapy was measured based on improvement in AP levels after therapy with PTX. AP levels at end of the study were compared with values at baseline by matched pairs t-test.p-value: 0.00195% CI: [-88.2, -26.4]Paired t-test
Secondary
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.
Time frame: 6 months
Population: Serum samples from both timepoints (entry and end of study) were available in only 16 of the 18 subjects who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Change in Alkaline Phosphatase After Pentoxifylline Therapy | Change in Serum Concentration of Tissue Inhibitor Metalloproteinase 1 (TIMP-1) After PTX Therapy. | -5.69 ng/mL | Standard Error 8.66 |
Comparison: Change from baseline in TIMP-1 levels was assessed by paired-t test. Distribution the variable values was assessed using normal probability plots. Matched pairs t-test was used to compare the change from baseline.p-value: 0.595% CI: [-24.14, 8.68]Paired t-test.
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Change in Alkaline Phosphatase After Pentoxifylline Therapy | Safety of Therapy in the Pilot Study of PTX Therapy in Patients With PBC Will be Assessed | 0 participants |