Ostrosky‐Zeichner 2014.
| Methods | Phase four multicentre, randomized, double‐blind, placebo‐controlled study with two arms (caspofungin prophylaxis versus placebo), followed by pre‐emptive therapy for subjects who develop proven or probable IFI. We considered only the prophylactic phase of the trial for the purpose of this review Duration of the study: August 2007 to March 2010 Patients excluded/patients randomized: 36/222 (15%) Sample size calculation/method description: Yes/Yes |
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| Participants |
Patients randomized: 222 Age (mean): 57.7 years (treatment group), 55.4 years (placebo group) Sex: 114 men, 72 women Inclusion criteria: patients admitted to the ICU during the preceding three days (minimum of 48 hours in ICU) and expected to stay in the ICU for at least another 48 hours, ventilated, received antibiotics, had a central line, and had one additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants) Exclusion criteria: allergy or intolerance to echinocandins, absolute neutrophil count < 500 cell/μL, AIDS, aplastic anaemia or chronic granulomatous disease, moderate or severe hepatic insufficiency, pregnancy or lactation, subjects likely to die within 24 hours of enrolment, antifungal therapy within 10 days prior to study, documentation of any active invasive fungal infection upon enrolment, previous enrolment in this study, and investigational agent within the 10 days prior entry Percentage post‐surgical: 25% Percentage colonized with Candida at baseline: not reported |
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| Interventions |
1. Caspofungin 70 mg/day IV loading dose followed by 50 mg/day IV (n = 117) 2. Placebo (n = 102) Intervention duration: throughout the ICU stay. When subjects met the primary endpoint (proven or probable IC), investigators were allowed to break the blind and subjects receiving placebo were started on therapy with caspofungin. Subjects receiving caspofungin were allowed to continue or to switch to other agents |
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| Outcomes | Mortality Proven IFI Suspected IFI Proven or suspected IFI Adverse events requiring cessation Follow‐up duration: until hospital discharge |
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| Type of antifungal treatment | Prophylaxis | |
| Funding sources | Quote: "This study was supported and sponsored by Merck & Co, Inc." | |
| Declaration of interest among the primary researchers | Quote: "L. O. Z. has received research grants from Merck, Astellas, Pfizer, and Associates of Cape Cod, and is a consultant and speaker for and has received honoraria from Merck, Astellas, and Pfizer. S. S. receives research funding from Astellas, Merck, and Pfizer, and is a member of the Merck Scientific Advisory Board. J. V. has received honoraria from Astellas and Forest; has received grants from Merck, Astellas, and Pfizer; and is a consultant for Astellas and Forest. R. Bed. has received research grants from Merck and Janssen Pharmaceuticals and has participated in ad hoc scientific advisory boards for Serono, ViiV, and Gilead Sciences. J. E. M. has received a research grant from Medline Industries and sits on an advisory board for Cepheid. S. G. R. has received research funding from Merck, Astellas, and Pfizer. C. W. is a full‐time employee of and own stocks in Merck. M. H. N. has received research support from Merck, Pfizer, and Astellas. C. A. K. has participated in other clinical trials from Merck. P. G. P has received grants and research support from Merck, Astellas, Gilead, and T2 Biosystems and is an ad hoc advisor for Merck, Astellas, Gilead, Scynexis, Viamet, and T2 Biosystems. All other authors report no potential conflicts" | |
| Notes |
Country: USA Setting: multicentre (15 centres), ICU |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: “Block randomization was stratified by APACHE II score (≤ 20 or > 20)” Comment: insufficient information to make a judgement about randomization sequence generation |
| Allocation concealment (selection bias) | Unclear risk | Comment: insufficient information to make a judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)" (Quoted from protocol) |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)" (Quoted from protocol). Comment: the blinding has been declared in the study and specified for trial registration. AE and severe AE managed by a data and safety monitoring board (DSMB) on treatment blinded fashion |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups |
| Selective reporting (reporting bias) | Low risk | Comment: the study protocol was available and all of the study prespecified (primary and secondary) outcomes that were of interest for review were reported in the prespecified way |
| Other bias | Low risk | The study appeared free of other sources of bias |