A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis.

BACKGROUND AND AIMS: Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life. STUDY QUESTION: No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner. STUDY DESIGN, MEASURES, AND OUTCOMES: A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subject's response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values. RESULTS: Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash). CONCLUSIONS: In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.

Parenteral bisphosphonates for osteoporosis in patients with primary biliary cirrhosis.

We aimed to describe the effects of parenteral bisphosphonates on bone mineral density (BMD) changes in primary biliary cirrhosis (PBC) patients with osteoporosis. Seventeen PBC patients with osteoporosis diagnosed between 1996 and 2005 were enrolled retrospectively. All patients received one of the following parenteral bisphosphonates: zoledronic acid, pamidronate disodium, or ibandronate sodium. The median (interquartile range) age of patients at osteoporosis diagnosis was 62.2 (56.4-67.9) and 94% were women. After treatment, percent change of lumbar spine bone mineral density (LS-BMD) and proximal femur BMD (PF-BMD) of patients with PBC was 2.9% and 0.4%, respectively. Eight patients (47%) showed a greater LS-BMD and/or PF-BMD with percent change of LS-BMD and PF-BMD of 8.7% and 0.8%, respectively. No serious adverse events were found. In PBC patients with osteoporosis, parenteral bisphosphonates can stabilize BMD for 47% of patients. More prospective studies are needed to evaluate the efficacy of specific parenteral bisphosphonates in patients with PBC and osteoporosis.

Moexipril for treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

Blockade of angiotensin II synthesis attenuates hepatic fibrosis in different experimental models of chronic liver injury. We evaluated the safety and efficacy of moexipril, an angiotensin-converting enzyme inhibitor, in patients with primary biliary cirrhosis (PBC) who have had a suboptimal response to ursodeoxycholic acid (UDCA). Twenty PBC patients on UDCA (13-15 mg/kg/day) therapy with an elevation of serum alkaline phosphatase at least twice the upper limit of normal were treated with oral moexipril 15 mg/day for one year. No significant changes in serum alkaline phosphatase (379 +/- 32 vs. 379 +/- 51), bilirubin (0.8 +/- 0.1 vs. 0.9 +/- 0.1), aspartate aminotransferase (60 +/- 8 vs. 63 +/- 9), and Mayo risk score (3.55 +/- 0.2 vs. 3.62 +/- 0.2) was associated with the treatment. Fatigue and health-related quality of life scores during treatment demonstrated a trend toward improvement. Moexipril was not clinically beneficial to PBC patients responding suboptimally to UDCA.

Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study.

OBJECTIVES: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of young adults that is associated with significant morbidity and mortality. No effective medical therapy is available. Minocycline has been found to exert biological effects independent of its antimicrobial properties, including anti-inflammatory activities such as inhibition of inducible nitric oxide synthase, upregulation of interleukin 10, and direct suppressive effect on B- and T-cell function. Minocycline may also inhibit cell death pathways by reducing both proapoptotic and proinflammatory enzyme activation. We sought to investigate the safety and efficacy of minocycline among patients with PSC. METHODS: We evaluated the efficacy of minocycline in patients with PSC in a pilot study. Sixteen patients with PSC were enrolled. Minocycline, 100 mg orally twice daily, was given for 1 year. RESULTS: A statistically significant improvement in serum alkaline phosphatase activity (330 U/l vs. 265 U/l, P=0.04) and Mayo risk score (0.55 vs. 0.02, P=0.05) occurred with treatment. Serum bilirubin and albumin remained essentially unchanged while on treatment. CONCLUSIONS: The results of this pilot study indicate that minocycline is reasonably well tolerated and potentially effective in patients with PSC. These findings might be explained by the anti-inflammatory and antiapoptotic properties of minocycline. Though the data presented are too preliminary to support the clinical use of minocycline in the treatment of PSC at this time, its use should be further investigated.

Tacrolimus for the treatment of primary sclerosing cholangitis.

BACKGROUND: Results from a pilot investigation with tacrolimus for primary sclerosing cholangitis (PSC) demonstrated biochemical improvement without excessive drug toxicity. To date, no confirmatory study has been performed. AIMS: We sought to determine the safety and efficacy of tacrolimus in PSC. METHODS: An open-label, phase II study of tacrolimus 0.05 mg/kg twice daily for 1 year was performed. Target whole-blood concentrations ranged between 3 and 7 ng/ml. RESULTS: A total of 16 patients were enrolled. The median age was 50 years (range, 28-68), with 31% being women. The median serum alkaline phosphatase was 903 U/l, AST 88 U/l, total bilirubin 0.9 mg/dl, and albumin 3.8 g/dl. Based primarily on drug-related adverse events, only eight (50%) patients completed 1 year of therapy. After 1 year of therapy, however, significant improvements in median serum alkaline phosphatase (903 vs. 483, P=0.0001) and AST levels (88 vs. 78, P=0.002) were observed in these patients. The median tacrolimus level in patients completing 1 year of therapy was 4.0 ng/ml. Drug-related adverse events, however, were responsible for 31% of participants withdrawing from the study. CONCLUSIONS: Despite significant improvements in serum alkaline phosphatase, oral tacrolimus is poorly tolerated in patients with PSC.

Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

BACKGROUND & AIMS: Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC. METHODS: Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy. RESULTS: Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients. CONCLUSIONS: MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.

Mycophenolate mofetil for the treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 +/- 581 U/L vs 912 +/- 463 U/L, p= 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.