Rifaximin plus lactulose versus lactulose alone for reducing the risk of HE recurrence.

BACKGROUND: The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes. METHODS: Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted. RESULTS AND CONCLUSION: Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.

Treatment-Free Interval: A Novel Approach to Assessing Real-World Treatment Effectiveness and Economic Impact Among Patients with Irritable Bowel Syndrome with Diarrhea.

INTRODUCTION: Objective assessment of treatment effectiveness using real-world claims data is challenging. This study assessed treatment-free intervals (TFI) as a proxy for treatment effectiveness, and all-cause healthcare costs among adult patients with irritable bowel syndrome with diarrhea (IBS-D) treated with rifaximin or eluxadoline in the USA. METHODS: Adult patients (18-64 years) with IBS-D and ≥ 1 rifaximin or eluxadoline prescription were identified in the IQVIA PharMetrics® Plus database (10/01/2015-12/31/2021) and classified into two mutually exclusive cohorts (i.e., rifaximin and eluxadoline). Index date was the date of rifaximin or eluxadoline initiation. Entropy-balanced baseline characteristics, TFI (periods of ≥ 30 consecutive days without IBS-D treatment), and healthcare costs were reported. Healthcare costs were compared between cohorts using mean cost differences. RESULTS: There were 7094 and 2161 patients in the rifaximin and eluxadoline cohorts, respectively. After balancing, baseline characteristics (mean age 44.1 years; female 72.4%) were similar between cohorts. A higher proportion of patients treated with rifaximin achieved a TFI of ≥ 30 days (76.2% vs. 66.7%), ≥ 60 days (67.0% vs. 47.0%), ≥ 90 days (61.0% vs. 38.7%), ≥ 180 days (51.7% vs. 31.0%), and ≥ 240 days (47.7% vs. 27.9%) compared to eluxadoline. Among patients with a TFI ≥ 30 days, mean TFI durations were 8.3 and 6.0 months for the rifaximin and eluxadoline cohorts. Mean all-cause healthcare costs were lower for rifaximin vs. eluxadoline ($18,316 vs. $23,437; p = 0.008), primarily driven by pharmacy costs ($7348 vs. $10,250; p < 0.001). In a simulated health plan of one million commercially insured lives, initiating 50% of patients on rifaximin instead of eluxadoline resulted in total cost savings of $2.1 million per year or $0.18 per-member-per-month. CONCLUSIONS: This real-world study suggests that TFI is a meaningful surrogate measure of treatment effectiveness in IBS-D. Patients treated with rifaximin had longer treatment-free periods and lower healthcare costs than patients treated with eluxadoline.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis.

Although ammonia is involved in the pathophysiology of hepatic encephalopathy (HE), the use of ammonia levels in clinical practice is problematic.1-3 For example, in a study of 551 patients with overt HE (OHE) receiving lactulose who had ammonia levels tested, only 60% had an increased ammonia level (defined as >72 µmol/L).2 Overall, there was no correlation observed between lactulose dose and whether ammonia levels were obtained (ie, presence/absence of increased ammonia level did not guide therapy), or between time to OHE resolution and ammonia levels.2 Additionally, there is substantial interlaboratory variability in sample handling and processing, which may affect ammonia measurements.4.

Impact of rifaximin use following an initial overt hepatic encephalopathy hospitalization on rehospitalization and costs.

AIM: To assess the impact of rifaximin (± lactulose) use following discharge of an initial overt hepatic encephalopathy (OHE) hospitalization on OHE rehospitalizations and healthcare costs in a real-world setting. METHODS: Adults (18-64 years) with an OHE hospitalization were identified from MarketScan® Commercial claims (Q4'15-Q2'20), classified into two mutually exclusive treatment cohorts (i.e. rifaximin and no rifaximin treatment), and further stratified into four subgroups based on decreasing quality of care (QoC; i.e. Type 1 - rifaximin without delay post-discharge; Type 2 - rifaximin with delay post-discharge; Type 3 - lactulose only post-discharge; Type 4 - no rifaximin/lactulose treatment post-discharge). The impact of rifaximin use on 30-day and annualized OHE hospitalizations and healthcare costs were assessed between cohorts and by the QoC subgroup. RESULTS: Characteristics were similar between the rifaximin (N = 1,452; Type 1: 1,138, Type 2: 314) and no rifaximin (N = 560; Type 3:337, Type 4: 223) treatment cohorts. The 30-day risk of OHE rehospitalization was lower for the rifaximin vs. no rifaximin treatment cohort (odds ratio 0.56, p < .01) and increased with decreasing QoC. The annual rate of OHE hospitalizations was 59% lower for the rifaximin treatment cohort (incidence rate ratio 0.41, p < .01) and increased with decreasing QoC. Compared to the no rifaximin treatment cohort, the rifaximin treatment cohort had higher pharmacy costs, lower medical costs, and no difference in total healthcare costs. LIMITATIONS: This was a claims-based study subject to common data limitations such as billing inaccuracies or omissions in coded claims. Total healthcare costs were reported from a payer's perspective, which do not capture indirect costs associated with patient burden. CONCLUSIONS: Initiation of rifaximin after an OHE hospitalization was associated with reduced OHE hospitalizations both in the 30-days following and annually. Further, reduced medical costs offset increased pharmacy costs, and no annual cost differences were observed between cohorts.

Rifaximin Treatment for Individual and Multiple Symptoms of Irritable Bowel Syndrome With Diarrhea: An Analysis Using New End Points.

PURPOSE: Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined. METHODS: Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed. FINDINGS: Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study. IMPLICATIONS: Rifaximin significantly improved multiple, concurrent IBS-D symptoms, using clinically relevant definitions of treatment response. Using a novel tri-symptom composite end point (ie, abdominal pain, bloating, fecal urgency), adults with IBS-D treated with a 2-week course of rifaximin were significantly more likely to be composite end point responders than those receiving placebo (≥30% or ≥40% threshold) for the three symptoms. Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements. CLINICALTRIALS: gov identifiers: NCT00731679, NCT00724126, and NCT01543178.

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).

Hospitalizations and healthcare costs associated with rifaximin versus lactulose treatment among commercially insured patients with hepatic encephalopathy in the United States.

AIMS: To assess healthcare costs and hospitalization rates associated with rifaximin therapy versus lactulose alone among patients at risk for hepatic encephalopathy (HE). METHODS AND MATERIALS: IBM Marketscan Commercial and Optum's de-identified Clinformatics Data Mart databases were used separately to identify commercially insured HE patients treated with rifaximin or lactulose alone, using an algorithm developed with clinical experts. HE-related hospitalizations were defined based on an algorithm using diagnosis codes and diagnosis-related group codes. HE-related/all-cause hospital admissions/days and healthcare costs were compared between rifaximin and lactulose episodes using incidence rate ratios and adjusted cost differences. RESULTS: In Marketscan, there were 13,515 [Optum: 5,217] rifaximin episodes and 9,946 [4,897] lactulose alone episodes included. Yearly rates of HE-related hospital admissions decreased by 33% [34%] when treated with rifaximin versus lactulose alone, and rates of HE-related hospital days similarly decreased by 43% [57%]. Yearly rates of all-cause hospital admissions decreased by 27% [27%]; rates of all-cause hospital days decreased by 33% [37%] during rifaximin episodes versus lactulose alone. This translated to $2,417 [$2,301] and $173 [$397] lower total mean medical costs and HE-related hospital costs per-patient-per-month, respectively (p < .05). Despite increased pharmacy costs associated with rifaximin, there was no change in total healthcare costs. Patients adherent to rifaximin incurred $2,891 [$2,340] lower total healthcare costs than non-adherent patients. In a simulated plan of 1 million lives, if 50% of HE patients treated with lactulose alone had rifaximin added on and were adherent to rifaximin therapy, the total cost savings would be $7.5 [$6.1] million per year ($0.62 [$0.50] per-member-per-month). CONCLUSIONS: Patients incurred significantly lower rates of HE-related and all-cause hospitalizations during rifaximin versus lactulose episodes, resulting in lower facility and professional costs. Cost savings may be possible if rifaximin adherence is improved in HE patients. LIMITATIONS: The study is subject to limitations common to claims-based analyses.

Abdominal Pain Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea.

INTRODUCTION: Abdominal pain is the principal symptom of irritable bowel syndrome (IBS). This analysis examined abdominal pain response in adults with IBS with diarrhea (IBS-D) receiving the nonsystemic antibiotic rifaximin. METHODS: In the Targeted Nonsystemic Antibiotic Rifaximin Gut-Selective Evaluation of Treatment for IBS-D 3 trial, adults with IBS-D received open-label rifaximin 550 mg 3 times daily for 2 weeks, followed by the 4-week post-treatment phase assessing abdominal pain and stool consistency response. Responders were followed for up to 18 additional weeks; patients with recurrence were randomly assigned to receive two 2-week courses of double-blind rifaximin 550 mg 3 times daily or placebo, separated by 10 weeks. Analyses evaluated mean weekly improvements from baseline (e.g., ≥30%, ≥40%, and ≥50%) in abdominal pain during the 4-week post-repeat-treatment phases. RESULTS: Of the 2,438 evaluable patients, 1,384 (56.8%) had abdominal pain response to open-label rifaximin (≥30% improvement from baseline in the mean weekly abdominal pain score during ≥2 of the first 4 weeks post-treatment). Weekly decrease (improvement) in responders' mean abdominal pain score (scale range, 0-10) from baseline ranged from -2.6 to -3.3 points during the 18-week follow-up. After the first double-blind repeat treatment, a significantly higher percentage of rifaximin-treated patients were abdominal pain responders (53.9% [172/319]) vs placebo (44.4% [134/302], P = 0.02), with similar results after the second repeat treatment (52.9% [155/293] vs 44.7% [123/275], respectively, P = 0.047). A significantly higher percentage of rifaximin-treated patients were weekly abdominal pain responders for ≥50% of the 18-week double-blind repeat treatment phase (47.9% [138/288] vs 35.9% [97/270], P = 0.004). DISCUSSION: Rifaximin is efficacious in improving abdominal pain in adults with IBS-D.

Lactulose Breath Testing as a Predictor of Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea.

OBJECTIVES: The nonsystemic antibiotic rifaximin is indicated for irritable bowel syndrome with diarrhea (IBS-D) in adults; however, determinants of response remain unclear. The utility of lactulose breath testing (LBT) in predicting response to rifaximin was examined. METHODS: Adults with IBS-D received open-label rifaximin 550 mg 3 times daily for 2 weeks, followed by a 4-week posttreatment assessment period. Thirteen centers prospectively participated in this substudy. LBT was conducted before (day 1) and after (day 14) therapy (breath samples obtained every 15 minutes; up to 240 minutes). Patient response (decrease from baseline of ≥30% in abdominal pain and ≥50% decrease in frequency of mushy/watery stool), symptom improvement, and the relationship of clinical outcomes to LBT results were assessed. RESULTS: A total of 93 patients were included; 62 (66.7%) had positive baseline LBT results. Overall, 48.4% (45/93) of patients responded to rifaximin; of these, 59.7% (37/62) had a positive baseline LBT vs 25.8% (8/31) with a negative LBT (P = 0.002; odds ratio 4.3, 95% confidence interval, 1.5-12.7). Patients with a positive baseline LBT result experienced significantly greater improvement from baseline in 6 of 7 individual IBS symptoms. LBT results after rifaximin therapy did not correlate with clinical response in the 86 patients with evaluable breath tests (P = 0.21); however, patients whose LBT results normalized after rifaximin had the highest response rate of 76.5% (13/17). DISCUSSION: A positive baseline LBT result predicted a higher likelihood of response to rifaximin in IBS-D, suggesting a gut microbiome modulatory mechanism of action for rifaximin.

Rifaximin has the potential to prevent complications of cirrhosis.

BACKGROUND: Cirrhosis-related complications are associated with poor prognosis. With our analyses, we examined the potential benefit of rifaximin in reducing the risk of developing cirrhosis-related complications. METHODS: Adults with cirrhosis and hepatic encephalopathy (HE) in remission were randomly assigned to receive rifaximin 550 mg twice daily or placebo for 6 months with concomitant lactulose permitted. Post hoc analyses examined time to cirrhosis-related complications (HE, spontaneous bacterial peritonitis (SBP), variceal bleeding, acute kidney injury/hepatorenal syndrome). Subgroup analyses evaluated efficacy for select baseline disease characteristics. RESULTS: Of patients receiving rifaximin (n = 140) and placebo (n = 159), 53.6% and 49.1%, respectively, had baseline Model for End-Stage Liver Disease (MELD) score ⩾ 12 and international normalized ratio (INR) ⩾ 1.2. Baseline ascites was observed in 36.4% (rifaximin) and 34.6% (placebo) of patients. In patients with MELD score ⩾ 12 and INR ⩾ 1.2, rifaximin reduced the relative risk (RR) of any first complication experienced during trial by 59% [hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.25-0.67; p < 0.001] versus placebo. For patients with baseline ascites, rifaximin reduced the RR of any first complication experienced during trial by 42% versus placebo (HR = 0.58, 95% CI: 0.34-1.0; p = 0.045). For some subgroups, there was a decrease in RR of complications of SBP, variceal bleeding, and acute kidney injury/hepatorenal syndrome with rifaximin versus placebo, although there were few events reported in the study. CONCLUSION: Rifaximin may reduce the incidence of cirrhosis-related complications and the recurrence of overt HE.[ClinicalTrials.gov identifier: NCT00298038.].

Repeat treatment with rifaximin improves irritable bowel syndrome-related quality of life: a secondary analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-D) impairs patient quality of life (QOL). Rifaximin is an oral, nonsystemic antibiotic indicated for IBS-D. The objective of this secondary analysis was to evaluate rifaximin retreatment on IBS-related QOL in patients with IBS-D. METHODS: Patients received open-label rifaximin 550 mg three times daily for 2 weeks. Clinical responders [simultaneously meeting weekly response criteria for abdominal pain (⩾30% improvement from baseline in mean weekly pain score) and stool consistency (⩾50% decrease from baseline in number of days/week with Bristol Stool Scale (BSS) type 6 or 7 stools) during ⩾2 of first 4 weeks posttreatment] who relapsed during an up to 18-week treatment-free observation phase were randomly assigned to receive two 2-week courses of double-blind rifaximin or placebo, separated by 10 weeks. A validated 34-item IBS-QOL questionnaire examined patient responses in 8 domains. RESULTS: The 2579 patients receiving open-label rifaximin experienced a mean improvement from baseline in IBS-QOL overall score of 54.9%. Responders to open-label rifaximin (n = 1074 of 2438 evaluable; 44.1%) had significantly greater improvement from baseline in IBS-QOL overall and all eight subdomain scores, including dysphoria, food avoidance, interference with activity, body image, and sexual function versus nonresponders at 4 weeks posttreatment (n = 1364; p < 0.001 for all comparisons). A significantly greater percentage of responders to open-label rifaximin achieved the minimally clinically important difference (MCID; ⩾14-point improvement from baseline) in the overall IBS-QOL score versus nonresponders [n = 561 (52.2%) versus n = 287 (21.0%); p < 0.0001]. Among 636 patients with IBS-D relapse, the MCID in the overall IBS-QOL score was achieved by a significantly greater percentage of patients receiving double-blind rifaximin versus placebo (38.6% versus 29.6%, respectively; p = 0.009). CONCLUSIONS: Open-label and blinded retreatment with a short course (2 weeks) of rifaximin improved IBS-QOL in patients with IBS-D [ClinicalTrials.gov identifier: NCT01543178].