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

Abstract

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.

Keywords: Antibacterial agents; Clostridium difficile infection; Cohort analyses; Randomised controlled trial; Recurrence.

Conflict of interest statement

Disclosure of potential conflict of interest

OAC has received research grants from Actelion, Arsanis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Duke University, F2G, Gilead, GSK, Leeds University, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Miltenyi, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres Therapeutics and The Medicines Company; and personal fees from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, IQVIA, Janssen Pharmaceuticals, Matinas, Menarini Ricerche, Merck/MSD, Paratek Pharmaceuticals, Pfizer, PSI, Scynexis, Seres Therapeutics, Summit, Tetraphase and Vical.

MJGTV is a consultant to Astellas Pharma, Berlin Chemie, MaaT Pharma and MSD/Merck; has served at the speakers’ bureaux of Astellas Pharma, Basilea, Falk Foundation, Gilead Sciences, Merck/MSD, Organobalance and Pfizer and received research funding from 3M, Astellas Pharma, DaVolterra, Gilead Sciences, Merck/MSD, Morphochem, Organobalance and Seres Therapeutics.

NA was an employee of Astellas Pharma, Inc. during the conduct of the study.

AG is a full-time employee of Astellas Pharma Europe Ltd.

AK is a full-time employee of Astellas Pharma Ltd. and has patents WO2015169451 A1 and EP17167541.6 pending to Astellas Pharma Europe Ltd.

GK is a consultant statistician for Astellas Pharma, Inc.

BG received personal and institutional fees from Astellas Pharma, Pfizer and MSD, non-financial support from Astellas Pharma and research grants from Combioxin and Fondation Santos Suarez.

Ethical approval

The study was conducted in accordance with local ethical committees’ regulations, the Declaration of Helsinki, and the International Council of Harmonisation Good Clinical Practice guidelines.

Informed consent

Patients provided written informed consent and could withdraw from the study at any time.

Figures

Fig. 1

Patient flow through the study

Fig. 2

Clinical outcomes of Clostridium difficile infection treatment with extended-pulsed fidaxomicin (EPFX) and vancomycin by presence of C. difficile PCR-ribotype 027 (present or absent), mFAS. a Sustained clinical cure (SCC) over time. b Clinical response. EOT, end of treatment; mFAS, modified full analysis set (all patients with confirmed CDI who were randomised and received at least one dose of study medication). P values were obtained from the chi-square test. Two days after EOT is day 27 for the EPFX arm and day 12 for the vancomycin arm; 30 days after EOT is day 55 for the EPFX arm and day 40 for the vancomycin arm