A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS: Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 µmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 µmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS: Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).

Treatment of Candida infections with amphotericin B lipid complex.

The efficacy and renal safety of amphotericin B lipid complex (ABLC) were assessed in >900 patients with candidiasis. Overall, a favorable clinical response (cured or improved) was observed in 61% of patients infected with Candida species only, in 62% of patients infected with C. albicans, and in 61% of patients infected with a non-albicans Candida species. Clinical responses were similar in patients infected with invasive C. albicans and non-albicans Candida species (63% and 62%, respectively). Similarly, response rates of 60% and 59% were observed in patients infected with noninvasive C. albicans and non-albicans Candida species, respectively. Compared with patients who received lower doses of ABLC, patients who required higher doses of ABLC because of more-virulent infections did not demonstrate significant renal impairment, as assessed by end-of-therapy changes in serum creatinine level from baseline (median, 0.1 mg/dL; range, -3.9 to 2.4 mg/dL), incidence of serum creatinine doubling (16%), and need for new dialysis (7%). These data indicate the safety and efficacy of ABLC in treating candidiasis.

Use of amphotericin B lipid complex in elderly patients.

OBJECTIVES: The safety and effectiveness of amphotericin B lipid complex (ABLC) treatment in elderly patients was investigated using a large multicenter database. METHODS: Data analysis was conducted on retrospectively collected patient data from 572 patients >65 years of age and 2930 patients < or =65 years of age treated for fungal infections at 160 North American hospitals. RESULTS: Patients were typically treated with ABLC for Candidiasis, multiple fungal pathogen infections and Aspergillosis, or were treated empirically. The median cumulative dose of ABLC in patients >65 years of age and those 65 years of age was similar (3000 and 3258 mg, respectively, P=0.127). Despite higher median pretreatment serum creatinine (S-Cr) among patients >65 years of age (1.7 mg/dl vs. 1.4 mg/dl, respectively), both groups showed only a 0.1mg/dl median S-Cr change from baseline by the end of therapy (P=0.525). Clinical response was 56 and 51%, respectively, in patients >65 years of age and patients 65 years of age or younger (P=0.049). CONCLUSIONS: This study suggests that ABLC can be safely and effectively used in the treatment of invasive fungal disease in elderly patients.

Retrospective study of the renal effects of amphotericin B lipid complex when used at higher-than-recommended dosages and longer durations compared with lower dosages and shorter durations in patients with systemic fungal infections.

BACKGROUND: Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg.d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages. OBJECTIVE: The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg.d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (or=4 ABLC doses according to a large, multicenter patient database, the Collaborative Exchange of Antifungal Research (CLEAR) registry. The safety profile of each dosage was evaluated using serum creatinine concentration (S-Cr) and calculated creatinine clearance (CCcr). RESULTS: A total of 1726 patients were studied. The HDos/LDur group included 309 patients and theLDos/SDur group included 1417 patients. The median ages of the HDos/LDur and LDos/SDur groups were 42 and 48 years, respectively (ranges, <1 to 83 and <1 to 95 years; P < 0.001); females comprised 51% and 42% of the 2 populations (P = 0.004); and 6% and 12% had solid tumors (P = 0.002). The HDos/LDur group was more likely than the LDos/SDur group to have been treated for multiple systemic fungal pathogen infections (16% and 9%, respectively) and for mold infections (28% and 12%, respectively) (both, P < 0.001). The median change in S-Cr from baseline was 0.1 mg/dL in both groups (range, -4.9 to 5 mg/dL in the HDos/LDur group and -3.96 to 4.7 mg/dL in the LDos/SDur group). No increased risk for renal dysfunction, as reflected in the median change from baseline in CCcr, was observed in either cohort (-3 mL/min [range, -118.65 to 69.03 mL/min] in the HDos/LDur group; -2.17 mL/min [range, -107.48 to 104.45 mL/min] in the LDos/SDur group). CONCLUSION: These data suggest that higher ABLC dosages appear to be as well tolerated as lower dosages, warranting further study of ABLC dosages >5 mg/kg.d for >12 days in the treatment of systemic fungal infections.