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Objective: We investigated the use of CAS for prophylaxis and pre-emptive therapy of IC in the ICU.
Methods: We conducted a multicenter, randomized, double-blind, placebo controlled trial of CAS 50mg IV/day as prophylaxis vs placebo for the duration of ICU stay in 222 adults who were hospitalized for at least 3 days, were ventilated, received antibiotics, had a central venous catheter at any time in the first 3 days, and had at least one other risk factor for IC: parenteral nutrition or dialysis (any of days 1 through 3 of ICU), major surgery, pancreatitis, or systemic steroids, or other immunosuppressive agents within 7 days prior to or on ICU admission. Subjects were followed daily for IC. (1,3)-b-D-glucan (BG) levels were monitored 2x/week. The primary endpoint was incidence of proven or probable IC by EORTC/MSG criteria. The endpoint was assessed by the investigator and a data review committee (DRC). Patients were followed for 14 days after completion of therapy. Patients that had IC at baseline or who met the endpoint received pre-emptive therapy with open label CAS. The MITT/prophylaxis population (primary efficacy analysis population), as defined by the DRC, included patients that received at least 1 dose of CAS and did not have IC at baseline (186). The safety/pre-emptive population included patients (219) that received at least 1 dose of CAS.
Results: Demographics, frequency of primary endpoint, and frequency of AEs are shown in the table. There were no significant differences in the secondary endpoints of mortality, initiation of other antifungals, hospital LOS, or ICU LOS.
Conclusions: We identified a selected population at high risk for IC. CAS was safe and trended to reduce the incidence of IC when used for prophylaxis or as part of a pre-emptive therapy strategy.
|
PLACEBO |
CAS |
P value* |
EFFICACY/PROPHYLAXIS ANALYSIS |
|
|
|
Population n |
84 |
102 |
|
Mean (+/-SD) age |
55.4 (16.8) |
57.7 (17.4) |
|
Male sex (%) |
59.5 |
62.7 |
|
Mean (+/-SD) APACHE II |
24.9 (8.6) |
25.0 (8.1) |
|
Proven and probable IC (%) by Investigator |
15.5 |
5.9 |
0.03 |
Proven and probable IC (%) by DRC |
16.7 |
9.8 |
0.14 |
Proven IC (%) by DRC |
4.8 |
1.0 |
0.1 |
|
|
|
|
SAFETY/PRE-EMPTIVE ANALYSIS |
|
|
|
Population n |
102 |
117 |
|
Mean (+/-SD) age |
56.7 (16.6) |
58.2 (17.6) |
|
Male sex (%) |
59.8 |
60.7 |
|
Mean (+/-SD) APACHE II |
25.1 (8.7) |
25.3 (8.0) |
|
Proven and probable IC (%) by Investigator |
25.5 |
13.7 |
0.02 |
Proven and probable IC (%) by DRC |
30.4 |
18.8 |
0.04 |
Proven IC (%) by DRC |
6.9 |
0.9 |
0.02 |
Patients with AE (%) |
84.5 |
89.8 |
|
Patients with drug-related AE (%) |
2.0 |
2.6 |
|
Patients with an SAE (%) |
27.5 |
28.2 |
|
Patients with a drug-related SAE (%) |
0 |
0.8 |
|
Patients with drug discontinuation due to drug-related AE (%) |
2.0 |
1.7 |
|
* Cochran-Mantel-Haenszel test stratified by APACHE II score.
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