Dosing of Rifaximin Soluble Solid Dispersion Tablets in Adults With Cirrhosis: 2 Randomized, Placebo-controlled Trials.

BACKGROUND & AIMS: Cirrhosis-related complications are a major burden. Rifaximin soluble solid dispersion (SSD) tablets (immediate-release [IR]; sustained extended-release [SER]) were designed to increase rifaximin water solubility. These analyses evaluate dosing for prevention of cirrhosis complication-related hospitalizations/mortality and overt hepatic encephalopathy (OHE) treatment.

METHODS

Two phase II, randomized, double-blind, placebo-controlled trials were conducted. Trial 1: outpatients with early decompensated cirrhosis randomized to placebo or rifaximin SSD once-nightly: IR 40 or 80 mg, SER 40 or 80 mg, or IR 80 mg plus SER 80 mg, for 24 weeks. Trial 2: inpatients with OHE randomized to lactulose plus placebo or rifaximin SSD: IR 40 mg once or twice daily or SER 80 mg once or twice daily for ≤14 days. Primary efficacy endpoint: time to cirrhosis complication-related hospitalization/all-cause mortality (Trial 1) or time to OHE resolution (Trial 2).

RESULTS

In Trial 1 (n = 516), no significant difference in time to cirrhosis complication-related hospitalization/all-cause mortality vs placebo. In a post hoc analysis, time to all-cause hospitalization/all-cause mortality was improved with IR 40 mg vs placebo (15.4% [12/78] vs 27.7% [26/94]; P = .03). A Trial 2 prespecified interim analysis (n = 71) showed lactulose plus rifaximin SSD IR 40 mg bid significantly reduced median time to OHE resolution (21.1 hours) vs lactulose plus placebo (62.7 hours; P = .02). Trial 2 was subsequently terminated.

CONCLUSION

Rifaximin SSD IR 40 mg may reduce hospitalizations in patients with cirrhosis and shorten duration of OHE during hospitalization-considered a negative finding, yet also hypothesis-generating. (ClinicalTrials.govNCT01904409; NCT03515044).