Extended-pulsed Fidaxomicin Research Articles

Cost-effectiveness of bezlotoxumab and fidaxomicin for initial Clostridioides difficile infection

ObjectivesTreatment of Clostridioides difficile infection (CDI) has undergone significant change in recent years with the introduction of fidaxomicin and bezlotoxumab. This study evaluated the cost-effectiveness of fidaxomicin and bezlotoxumab for initial CDI compared with standard therapy with oral vancomycin. MethodsA Markov model with eight health states was built based on transition probabilities, costs and health utilities derived from literature to evaluate the cost-effectiveness of standard fidaxomicin, bezlotoxumab plus vancomycin, and extended-pulsed fidaxomicin versus standard oral vancomycin over a lifetime horizon from the US societal perspective. ResultsFor overall CDI treatment, oral vancomycin had a cost of $39 178 and was associated with a gain of 11.64 quality-adjusted life-years (QALYs). Extended-pulsed fidaxomicin had a higher QALY gain of 11.65 at a lower cost of $37 613, and therefore was dominant over vancomycin. Standard fidaxomicin had a QALY gain of 11.94 versus vancomycin at an incremental cost of $495 per QALY. Bezlotoxumab plus vancomycin led to a QALY gain of 11.77 at an incremental cost of $17 746 per QALY. At the willingness-to-pay (WTP) threshold of $150 000 per QALY, extended-pulsed fidaxomicin, bezlotoxumab plus vancomycin and standard fidaxomicin were more cost-effective compared with vancomycin alone, yielding incremental net monetary benefits of $3248, $17 011 and $44 308, respectively. One-way sensitivity analysis suggested that the probabilities of sustained cure from the initial episode were the most sensitive inputs, and results were overall not particularly sensitive to any drug costs. ConclusionsBased on a WTP threshold of $150 000, standard fidaxomicin was estimated to be the most cost-effective treatment. Standard-of-care vancomycin was dominated by extended-pulsed fidaxomicin for treating an episode of CDI and preventing further recurrence, and the addition of bezlotoxumab to vancomycin was dominated by standard fidaxomicin.

Microbiological Characterization and Clinical Outcomes After Extended-Pulsed Fidaxomicin Treatment for Clostridioides difficile Infection in the EXTEND Study.

Background Clostridioides (Clostridium) difficile infection (CDI) is diagnosed using clinical signs and symptoms plus positive laboratory tests. Recurrence of CDI after treatment is common, and coinfection with other enteric pathogens may influence clinical outcomes.MethodsWe aimed to assess rates of C difficile positivity, by enzyme-linked immunosorbent assay (ELISA) toxin A/B and BioFire FilmArray, and the effect of enteric coinfection on clinical outcomes, using samples from the EXTEND study of extended-pulsed fidaxomicin (EPFX) versus standard vancomycin.ResultsAll 356 randomized and treated patients tested positive for C difficile toxin A/B by local tests; a majority (225 of 356, 63.2%) also tested positive by both ELISA and BioFire. Most stool samples taken at screening tested positive for C difficile only using BioFire (EPFX: 112 of 165, 69.7%; vancomycin: 118 of 162, 72.8%). Of the 5 patients who failed treatment and had stool samples available, all (1) had tested negative for C difficile by BioFire at screening and (2) were negative by ELISA at time of treatment failure. When analyzed by BioFire results at screening, rates of sustained clinical cure at 30 days after end of treatment were numerically higher with EPFX than with vancomycin for almost all patients, except for those who tested negative for C difficile but positive for another pathogen. However, these outcome differences by presence of coinfection did not reach statistical significance. Whole-genome sequencing analysis determined that 20 of 26 paired samples from patients with recurrence were reinfections with the same C difficile strain.ConclusionsTesting for presence of copathogens in clinical trials of antibiotics could help to explain clinical failures.

Extended-pulsed fidaxomicin cost effective for CDI

Extended-pulsed fidaxomicin cost effective for CDI

Extended-pulsed fidaxomicin versus vancomycin in patients 60\xa0years and older with Clostridium difficile infection: cost-effectiveness analysis in Spain

The cost of treating Clostridium difficile infection (CDI) in Spain is substantial. Findings from the randomised, controlled, open-label, phase 3b/4 EXTEND study showed that an extended-pulsed fidaxomicin (EPFX) regimen was associated with improved sustained clinical cure and reduced recurrence of CDI versus vancomycin in patients aged 60 years and older. We assessed the cost-effectiveness of EPFX versus vancomycin for the treatment of CDI in patients aged 60 years and older from the perspective of the National Health System (NHS) in Spain. We used a Markov model with six health states and 1-year time horizon. Health resources, their unit costs and utilities were based on published sources. Key efficacy data and transition probabilities were obtained from the EXTEND study and published sources. A panel of Spanish clinical experts validated all model assumptions. In the analysis, 0.638 and 0.594 quality-adjusted life years (QALYs) per patient were obtained with EPFX and vancomycin, respectively, with a gain of 0.044 QALYs with EPFX. The cost per patient treated with EPFX and vancomycin was estimated to be €10,046 and €10,693, respectively, with a saving of €647 per patient treated with EPFX. For willingness-to-pay thresholds of €20,000, €25,000 and €30,000 per QALY gained, the probability that EPFX was the most cost-effective treatment was 99.3%, 99.5% and 99.9%, respectively. According to our economic model and the assumptions based on the Spanish NHS, EPFX is cost-effective compared with vancomycin for the first-line treatment of CDI in patients aged 60 years and older.

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection: EXTEND study subgroup analyses

Poor outcomes following Clostridium difficile infection (CDI) have been associated with advanced age, presence of cancer and C. difficile PCR-ribotype 027. The impact of baseline risk factors on clinical outcomes was evaluated using data from the EXTEND study, in which rate of sustained clinical cure (SCC) in the overall population was significantly higher with an extended-pulsed fidaxomicin (EPFX) regimen than with vancomycin. Patients aged ≥ 60 years received EPFX (fidaxomicin 200 mg twice daily, days 1–5; once daily on alternate days, days 7–25) or vancomycin (125 mg four times daily, days 1–10). We analysed outcomes by advanced age, cancer diagnosis, CDI severity, prior CDI occurrence and infection with PCR-ribotype 027. The primary endpoint was SCC 30 days after end of treatment (EOT; clinical response at test-of-cure with no subsequent recurrence). SCC rates 30 days after EOT did not differ significantly between EPFX (124/177, 70.1%) and vancomycin (106/179, 59.2%) regardless of age, cancer diagnosis, CDI severity and prior CDI. In patients with PCR-ribotype 027, SCC rate 30 days after EOT was significantly higher with EPFX (20/25, 80%) than with vancomycin (9/22, 40.9%) (treatment difference, 39.1%; 95% CI, 13.2–64.9; P = 0.006). Subgroup analyses from the EXTEND study suggest that EPFX is efficacious as a potential treatment for CDI regardless of age, cancer diagnosis, infection with PCR-ribotype 027, CDI severity or prior CDI. ClinicalTrials.gov identifier: NCT02254967.

1982. Multiplex PCR-Based Analysis of Enteric Pathogens in Faecal Samples from Patients with Clostridium difficile Infection in the Randomized, Controlled EXTEND Study Comparing the Efficacy of Extended-Pulsed Fidaxomicin With Vancomycin Therapy

BackgroundExtended-pulsed fidaxomicin (EPFX) was equivalent to standard vancomycin (SV) for resolving Clostridium difficile infection (CDI) in the EXTEND study. Sustained clinical cure (SCC) at 30 days after end of treatment (EOT) was achieved in 124/177 (70%) patients receiving EPFX vs. 106/179 (59%) patients receiving SV (difference 11%; P = 0.030). The BioFire platform, a multiplex PCR-based method, was used to detect possible enteric co-pathogens in patients from EXTEND.MethodsPatients aged ≥60 years with positive local test for CDI were randomized (1:1) to receive either EPFX (200 mg tablets, twice daily on Days 1–5 and once daily on alternate days on Days 7–25) or SV (125 mg capsules, four times daily on Days 1–10). Stool samples were collected from all patients at screening and analysed using the BioFire FilmArray Gastrointestinal (GI) panel (Biomérieux). The primary endpoint was the rate of SCC at 30 days after EOT, defined as clinical response (determined by the investigator) and no CDI recurrence. Patients were grouped according to BioFire results, and clinical outcomes were then compared using the chi-square test and logistic regression analyses.ResultsAt screening, all patients tested positive for C. difficile toxin A/B by local laboratory test, and 286/332 patients tested positive for C. difficile by BioFire (Figure 1). SCC rates at 30 days after EOT, by baseline presence/absence of enteric co-pathogens, are given in Figure 1, and logistic regression analyses of SCC at 30 days after EOT are given in Table 1. ConclusionSCC-related treatment differences were evident for patients with BioFire-positive C. difficile vs. those positive for other enteric pathogens, but were not statistically significant due to low patient numbers in comparator groups.Disclosures M. Wilcox, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Research grant, Speaker honorarium and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. O. A. Cornely, Astellas Pharma: Grant Investigator, Lecture speaker and Scientific Advisor, Research grant, Speaker honorarium and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. B. Guery, Astellas Pharma: Consultant, Consulting fee and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. C. Longshaw, Astellas Pharma: CL was a full-time employee of Astellas Pharma, Inc., during the study conduct and is now an employee of Shionogi Europe Ltd.; he also has a patent WO2015169451 A1 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. A. Georgopali, Astellas Pharma: Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. A. Karas, Astellas Pharma: AK has patents WO2015169451 A1 and EP17167541.6 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. G. Kazeem, Astellas Pharma: Independent Contractor, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. J. A. Palacios-Fabrega, Astellas Pharma: AP-F has a patent EP17167541.6 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. M. J. G. T. Vehreschild, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Grant recipient and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas.

1952. Evaluation of Relapse and Reinfection Using Whole-Genome Sequencing of Clostridium difficile Isolates From Elderly Patients With C. difficile Infection (CDI) in the EXTEND Randomized, Controlled, Comparative Study of Extended-Pulsed Fidaxomicin and Vancomycin for the Treatment of CDI

BackgroundThe EXTEND study demonstrated reduced 90-day recurrence rates for an extended-pulsed regimen of fidaxomicin (EPFX) vs. standard vancomycin (SV) in the treatment of Clostridium difficile infection (CDI): treatment difference −13%, P = 0.00073.1 Whole-genome sequencing (WGS) is used to differentiate between same-strain relapse and new-strain reinfection of CDI. We used WGS of paired C. difficile samples from patients with CDI recurrence in the EXTEND study to assess EPFX and SV in relation to relapse and reinfection.MethodsPatients aged ≥60 years with CDI were randomized (1:1) to receive either EPFX (fidaxomicin 200 mg tablets, twice daily on Days 1–5 and once daily on alternate days on Days 7–25) or SV (125 mg capsules, four times daily on Days 1–10). Paired stool samples were collected from all patients at screening and from patients with recurrence after test-of-cure (TOC). Recurrence was defined as diarrhoea occurring to a greater extent than the frequency recorded at TOC, and confirmed positive for C. difficile toxin A/B and requiring further CDI therapy. C. difficile isolates from paired samples underwent WGS and single nucleotide variant (SNV) difference analysis. Paired samples with ≤2 SNV differences were considered relapses, paired samples with >10 SNV differences were considered reinfection, and those with >2 but ≤10 SNV differences (or without WGS) were considered indeterminate.ResultsAt Day 90, 11/177 (6%) patients in the EPFX arm and 34/179 (19%) patients in the SV arm had CDI recurrence. Of these, samples from 7/11 EPFX- and 19/34 SV-treated patients were available for paired WGS analysis. SNV analysis showed that most CDI recurrences were new-strain reinfections (table). ConclusionMost recurrences were reinfections, but small sample sizes limited definitive conclusions.Reference1. Guery et al. (2017). Lancet Inf Dis 18:296–307.Disclosures M. Wilcox, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Research grant, Speaker honorarium and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. O. A. Cornely, Astellas Pharma: Grant Investigator, Lecture speaker and Scientific Advisor, Research grant, Speaker honorarium and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. B. Guery, Astellas Pharma: Consultant, Consulting fee and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. C. Longshaw, Astellas Pharma: CL was a full-time employee of Astellas Pharma, Inc., during the study conduct and is now an employee of Shionogi Europe Ltd.; he also has a patent WO2015169451 A1 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas and Salary. A. Georgopali, Astellas Pharma: Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. A. Karas, Astellas Pharma: AK has patents WO2015169451 A1 and EP17167541.6 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. G. Kazeem, Astellas Pharma: Independent Contractor, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. J. A. Palacios-Fabrega, Astellas Pharma: AP-F has a patent EP17167541.6 pending. and Employee, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. M. J. G. T. Vehreschild, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Grant recipient and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas.

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial

Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin. In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25) or vancomycin (125 mg oral capsules, four times daily on days 1-10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967. Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0-20·7], p=0·030; odds ratio 1·62 [95% CI 1·04-2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection. Astellas Pharma, Inc.

Sub-group Analyses from the EXTEND Study: a Randomised, Controlled, Open-Label, Phase III/IV Study Comparing the Efficacy of Extended-Pulsed Fidaxomicin with Standard Vancomycin Therapy for Sustained Clinical Cure of Clostridium difficile Infection in an Older Population

Sub-group Analyses from the EXTEND Study: a Randomised, Controlled, Open-Label, Phase III/IV Study Comparing the Efficacy of Extended-Pulsed Fidaxomicin with Standard Vancomycin Therapy for Sustained Clinical Cure of Clostridium difficile Infection in an Older Population