TY - JOUR
T1 - A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation
AU - Mullane, Kathleen M.
AU - Winston, Drew J.
AU - Nooka, Ajay
AU - Morris, Michele I.
AU - Stiff, Patrick
AU - Dugan, Michael J.
AU - Holland, Henry
AU - Gregg, Kevin
AU - Adachi, Javier A.
AU - Pergam, Steven A.
AU - Alexander, Barbara D.
AU - Dubberke, Erik R.
AU - Broyde, Natalya
AU - Gorbach, Sherwood L.
AU - Sears, Pamela S.
N1 - Funding Information:
Financial support. This work was supported by Optimer Pharmaceuticals, Inc., and Cubist Pharmaceuticals (now a subsidiary of Merck & Co., Inc.), which provided financial support and investigational drug supplies for the study. Medical writing and editorial assistance were provided by Kim M. Strohmaier; Mary E Hanson, PhD; and Carol Zecca, all employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Potential conflicts of interest. K. M. M., D. J. W., A. N., M. I. M., P. S., M. J. D., H. H., K. G., J. A. A., S. A. P., B. D. A., and E. R. D. received research grants from Optimer Pharmaceuticals, Inc., and Cubist Pharmaceuticals (now a subsidiary of Merck & Co., Inc.) for this study. D. J. W. has received research grants from Merck for studies of inactivated varicella-zoster vaccine and letermovir. A. N. has received consultant fees from Amgen, Novartis, and Spectrum. M. J. D. has received research grants from Merck for studies of letermovir. S. A. P. has served as consultant for Merck, Optimer/Cubist, and Chimerix, and received research grants for clinical trials with these entities. E. R. D. has received consultant fees from Sanofi Pasteur, Rebiotix, GSK, Merck, Valenva, and Summit. S. L. G. was Editor-in-Chief of Clinical Infectious Diseases until 31 December 2016. N. B. and P. S. S. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and may own stock and/or stock options in the company. M. I. M. has received payments from Novartis and Chimerix. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.
PY - 2019/1/7
Y1 - 2019/1/7
N2 - Background. Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. Methods. In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Results. Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. Conclusions. While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients.
AB - Background. Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. Methods. In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Results. Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. Conclusions. While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients.
KW - Clostridium difficile-associated diarrhea
KW - Fidaxomicin
KW - Hematopoietic stem-cell transplantation
KW - Prophylaxis
UR - http://www.scopus.com/inward/record.url?scp=85059460982&partnerID=8YFLogxK
U2 - 10.1093/cid/ciy484
DO - 10.1093/cid/ciy484
M3 - Article
C2 - 29893798
AN - SCOPUS:85059460982
SN - 1058-4838
VL - 68
SP - 196
EP - 203
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 2
ER -