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.

Varices in early histological stage primary biliary cirrhosis.

BACKGROUND/GOALS: Esophageal varices (EV) in early histological stages of primary biliary cirrhosis (PBC) have been recognized but not well defined. We sought to determine the prevalence, clinical characteristics, and predictors of EV in early-stage PBC, as well as to evaluate the effectiveness of recent guidelines regarding EV screening in PBC patients. STUDY: We retrospectively reviewed the charts of 325 PBC patients who had undergone complete evaluation before enrollment into 2 large clinical trials at the Mayo Clinic. RESULTS: Nineteen percent (62/325) of our patient population had EV on esophagogastroduodenoscopy; 6% (8/127) of early-stage PBC patients had EV. Ninety five percent of our PBC patients with varices met at least one of the following conditions: male sex, low albumin (<3.5 g/dL), elevated bilirubin level (≥1.2 mg/dL), and/or prolonged prothrombin time (≥12.9 s). The sensitivity and specificity of these variables in combination to predict the presence of varices were 95% and 55%, respectively. Serum bilirubin ≥1.2 mg/dL and albumin <3.5 were independent predictors of varices with hazard values of 5.4 and 3.5 respectively. CONCLUSIONS: EV can occur in a minority of early-stage PBC patients. Various models may be used to identify PBC patients who are candidates for screening esophagogastroduodenoscopy for EV. Based on adequate performance and its simplicity, we propose that male sex, low albumin, elevated bilirubin, and/or prolonged prothrombin time be used as a model to noninvasively predict EV. Further validation is required.

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.

Serum lipids in primary sclerosing cholangitis.

BACKGROUND: Limited data are available regarding the serum lipids in primary sclerosing cholangitis. AIMS: To determine the lipid levels in patients with primary sclerosing cholangitis. METHODS: We monitored the serum lipid levels annually for up to 6 years in 157 patients included in three previous trials of ursodeoxycholic acid. RESULTS: The baseline lipid values were: total cholesterol=207 mg/dL (127-433); high-density lipoprotein=56 mg/dL (26-132); low-density lipoprotein=129 mg/dL (48-334); triglycerides=102 mg/dL (41-698). Cirrhotic stage was associated with lower levels of total cholesterol (186 mg/dL vs. 217 mg/dL, p=.02). A significant correlation between the liver biochemistries and total and low-density lipoprotein cholesterol levels was observed. Ursodeoxycholic acid, as compared to placebo, significantly decreased total (-27 mg/dL vs. 22 mg/dL, p=.0004) and low-density lipoprotein cholesterol (-24 mg/dL vs. 17 mg/dL, p=.0001). After extended follow-up, small changes in the lipid levels were noticed. The incidence of coronary artery disease was 4%. CONCLUSIONS: Our findings suggest that the lipid levels in primary sclerosing cholangitis are often above levels where treatment with lipid-lowering agents is recommended. However, primary sclerosing cholangitis patients seem to have no elevated risk for cardiovascular events. The correlation of total and low-density lipoprotein cholesterol with liver biochemistries implies that mechanisms linked to cholestasis may regulate cholesterol metabolism.

Fatigue in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis of the liver and may need liver transplantation in the late stage of disease. Fatigue and pruritus are the most common symptoms of PBC, but the majority of patients are asymptomatic at first presentation. There is no specific treatment for fatigue in PBC, but modafinil has shown some potential beneficial effects, such as increased energy levels and decreased total sleep time. This Review article discusses the natural history and the measurement of fatigue in patients with PBC. The central and the peripheral mechanisms that have been suggested for the pathogenesis of fatigue in PBC are also discussed and treatment options are reviewed.

Silymarin in the treatment of patients with primary sclerosing cholangitis: an open-label pilot study.

No effective medical therapy is available for patients with primary sclerosing cholangitis (PSC). We evaluated the safety and estimated the efficacy of silymarin in patients with PSC in a pilot study. Thirty patients with PSC were enrolled. Silymarin, 140 mg orally three times daily, was given for 1 year. A statistically significant improvement in serum alkaline phosphatase activity (1131 +/- 216 vs. 861 +/- 139, P = 0.007), and aspartate aminotransferase (AST) levels (116 +/- 15 vs. 83 +/- 11, P = 0.01) occurred with treatment. Serum bilirubin levels were not significantly affected by the treatment, while serum albumin and the Mayo risk score remained essentially unchanged. Overall, 34% of patients had a positive response to silymarin as defined by > or =50% improvement or normal status in liver tests. The results of this pilot study warrant further evaluation of silymarin in patients with PSC in a large-scale, controlled trial.

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.

Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial.

Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks' duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a > or =50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.

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.

Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial.

Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.

Nonalcoholic Fatty liver disease.

Nonalcoholic fatty liver disease is a condition gaining increasing recognition as a cause of cirrhosis and end-stage liver disease. The condition appears identical to alcoholic liver disease histologically, yet occurs in patients with negligible alcohol intake. Nonalcoholic fatty liver disease covers a spectrum of diseases ranging from simple fatty deposition in the liver to fat and inflammation and finally to fibrosis and cirrhosis. Conditions most frequently found in association with nonalcoholic fatty liver disease include obesity, Type 2 diabetes, and hyperlipidemia. Although the exact etiology of nonalcoholic fatty liver disease is not clear, insulin resistance is thought to play an important factor. Patients typically present with asymptomatic serum aminotransferase elevations of 2-3 times normal. Symptoms may include fatigue and abdominal pain. The clinical course is difficult to predict due to a lack of research in the natural history of the disease. It is known a percentage of patients progress to end-stage liver disease and may require liver transplantation. No medical treatment has been found to be totally effective. Patients who are overweight or obese should be encouraged in gradual weight reduction that has been associated with improvement in liver test abnormalities.

Natural history of pruritus in primary biliary cirrhosis.

The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.

Pirfenidone in the treatment of primary sclerosing cholangitis.

Our aim was to evaluate the safety and assess the efficacy of pirfenidone, an antifibrotic drug, in patients with primary sclerosing cholangitis (PSC). Twenty-four patients with PSC were enrolled in this pilot study. Oral pirfenidone, 2400 mg daily, was given for one year. Liver biochemistries were determined at three-month intervals. The Mayo risk score was calculated, and liver biopsy and endoscopic cholangiography were performed at entry and at one year of treatment. No significant changes in liver biochemistries were noted at the end of the treatment period or at any of the three-month intervals. The Mayo risk score did not change significantly, and no significant changes were noted in the degree of inflammation, fibrosis, histologic stage of disease, or cholangiographic findings at the end of the treatment period. Adverse events occurred in 20/24 (83%) patients, but disappeared shortly after pirfenidone was discontinued. Pirfenidone did not benefit patients with PSC, and it was frequently associated with adverse events. The results of this pilot study discourage further trials of pirfenidone in patients with PSC.