title: Impact of alternate definitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study.
abstract: BACKGROUND
  Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates.
  
  
  METHODS
  The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients.
  
  
  RESULTS
  In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients.
  
  
  CONCLUSIONS
  Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.
authors.affiliation: University Hospital St. Radboud, Nijmegen, The Netherlands. B.dePauw@abti.umcn.nl
authors.forename: B E
authors.initials: BE
authors.lastname: de Pauw
authors.forename: C A
authors.initials: CA
authors.lastname: Sable
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: R J
authors.initials: RJ
authors.lastname: Lupinacci
authors.forename: M R
authors.initials: MR
authors.lastname: Bourque
authors.forename: B A
authors.initials: BA
authors.lastname: Wise
authors.forename: B-Y
authors.initials: BY
authors.lastname: Nguyen
authors.forename: M J
authors.initials: MJ
authors.lastname: DiNubile
authors.forename: H
authors.initials: H
authors.lastname: Teppler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000666:Amphotericin B / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D000077336:Caspofungin; D004311:Double-Blind Method; D054714:Echinocandins; D005260:Female; D005334:Fever / Q000209:etiology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D055666:Lipopeptides; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D009503:Neutropenia / Q000209:etiology / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D012307:Risk Factors; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000666:Amphotericin B; D000077336:Caspofungin