Candidemia and other Candida infections (intra-abdominal abscess, and peritonitis)
The safety and efficacy of ERAXIS were evaluated in a Phase 3, randomized, double-blind
study of patients with candidemia and/or other forms of invasive candidiasis. Patients
were randomized to receive once daily IV ERAXIS (200 mg loading dose followed by
100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400
mg maintenance dose). Patients were stratified by APACHE II score (≤ 20 and > 20)
and the presence or absence of neutropenia. Patients with Candida endocarditis,
osteomyelitis or meningitis, or those with infection due to C. krusei, were
excluded from the study. Treatment was administered for at least 14 and not more
than 42 days. Patients in both study arms were permitted to switch to oral fluconazole
after at least 10 days of intravenous therapy, provided that they were able to tolerate
oral medication, were afebrile for at least 24 hours, and the last blood cultures
were negative for Candida species.
Patients who received at least one dose of study medication and who had a positive
culture for Candida species from a normally sterile site before entry into
the study (modified intent-to-treat [MITT] population) were included in the primary
analysis of global response at the end of IV therapy. A successful global response
required clinical cure or improvement (significant, but incomplete resolution of
signs and symptoms of the Candida infection and no additional antifungal
treatment), and documented or presumed microbiological eradication. Patients with
an indeterminate outcome were analyzed as failures in this population.
Two hundred and fifty-six patients were randomized and received at least one dose
of study medication. The median duration of IV therapy was 14 and 11 days in the
ERAXIS and fluconazole arms, respectively. For those who received oral fluconazole,
the median duration of oral therapy was 7 days for the ERAXIS arm and 5 days for
the fluconazole arm.
Patient disposition is presented in Table 4.
Table 4. Patient Disposition and Reasons for Discontinuation in Candidemia and other
Candida infection study
Two hundred and forty-five patients (127 ERAXIS, 118 fluconazole) met the criteria
for inclusion in the MITT population. Of these, 219 patients (116 ERAXIS, 103 fluconazole)
had candidemia only. Risk factors for candidemia among patients in both treatment
arms in this study were: presence of a central venous catheter (78%), receipt of
broad-spectrum antibiotics (69%), recent surgery (42%), recent hyperalimentation
(25%), and underlying malignancy (22%). The most frequent species isolated at baseline
was C. albicans (61.6%), followed by C. glabrata (20.4%), C. parapsilosis
(11.8%) and C. tropicalis (10.6%). The majority (97%) of patients were non-neutropenic
(ANC > 500) and 81% had APACHE II scores less than or equal to 20.
Global success rates in patients with candidemia and other Candida infections
are summarized in Table 5.
Table 5. Efficacy Analysis: Global Success in patients with Candidemia and other
Candida infections (MITT Population)
Table 6 presents outcome and mortality data for the MITT population.
Table 6. Outcomes & Mortality in Candidemia and other Candida Infections
Esophageal Candidiasis
ERAXIS was evaluated in a double-blind, double-dummy, randomized Phase 3 study.
Three hundred patients received ERAXIS (100 mg loading dose IV on Day 1 followed
by 50 mg/day IV ) and 301 received oral fluconazole (200 mg loading dose on Day
1 followed by 100 mg/day). Treatment duration was 7 days beyond resolution of symptoms
for a minimum of 14 and a maximum of 21 days.
Of the 442 patients with culture confirmed esophageal candidiasis, most patients
(91%) had C. albicans isolated at the baseline.
Treatment groups were similar in demographic and other baseline characteristics.
In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both
groups the median time to resolution of symptoms was 5 days and the median duration
of therapy was 14 days.
The primary endpoint was endoscopic outcome at end of therapy (EOT). Patients were
considered clinically evaluable if they received at least 10 days of therapy, had
an EOT assessment with a clinical outcome other than 'indeterminate', had an endoscopy
at EOT, and did not have any protocol violations prior to the EOT visit that would
affect an assessment of efficacy.
An endoscopic success, defined as cure (endoscopic grade of 0 on a 4 point severity
scale) or improvement (decrease of one or more grades from baseline), was seen in
225/231 (97.4%) ERAXIS-treated patients and 233/236 (98.7%) fluconazole-treated
patients (Table 7). The majority of these patients were endoscopic cures (grade=0).
Two weeks after completing therapy, the ERAXIS group had significantly more endoscopically-documented
relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively
(Table 7).
Table 7. Endoscopy Results in Patients with Esophageal Candidiasis (Clinically Evaluable
Population)
Clinical success (cure or improvement in clinical symptoms including odynophagia/dysphagia
and retrosternal pain) occurred in 229/231 (99.1%) of the ERAXIS-treated patients
and 235/236 (99.6%) of the fluconazole-treated patients at the end of therapy. For
patients with C. albicans, microbiological success occurred in 142/162 (87.7%)
of the ERAXIS-treated group and 157/166 (94.6%) of the fluconazole-treated group
at the end of therapy. For patients with Candida species other than C. albicans,
success occurred in 10/12 (83.3%) of the ERAXIS-treated group and 14/16 (87.5%)
of the fluconazole-treated group.