Adults Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis) Trial
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 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 in the intent-to-treat (ITT) population were randomized and received at least one dose of study medication. In ERAXIS-treated patients, the age range was 16–89 years, the gender distribution was 50% male and 50% female, and the race distribution was 71% White, 20% Black/African American, 7% Hispanic, 2% other races. 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 9.
Table 9: Patient Disposition and Reasons for Discontinuation in Candidemia and other Candida Infections Study | ERAXIS | Fluconazole |
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| n (%) | n (%) |
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Treated patients | 131 | 125 |
Patients completing study through 6 week follow-up | 94 (72) | 80 (64) |
DISCONTINUATIONS FROM STUDY MEDICATION |
Total discontinued from study medication | 34 (26) | 48 (38) |
Discontinued due to adverse events | 12 (9) | 21 (17) |
Discontinued due to lack of efficacy | 11 (8) | 16 (13) |
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 (62%), followed by C. glabrata (20%), C. parapsilosis (12%) and C. tropicalis (11%). 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 10.
Table 10: Efficacy Analysis: Global Success in patients with Candidemia and other Candida Infections (MITT Population)Time-point | ERAXIS (N=127) n (%) | Fluconazole (N=118) n (%) | Treatment Difference*, % (95% C.I.) |
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|
End of IV Therapy | 96 (75.6) | 71 (60.2) | 15.4 (3.9, 27.0) |
End of All Therapy† | 94 (74.0) | 67 (56.8) | 17.2 (2.9, 31.6)‡ |
2 Week Follow-up | 82 (64.6) | 58 (49.2) | 15.4 (0.4, 30.4)‡ |
6 Week Follow-up | 71 (55.9) | 52 (44.1) | 11.8 (-3.4, 27.0)‡ |
Table 11 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.
Table 11: Global Response and Mortality in Candidemia and other Candida Infections | ERAXIS | Fluconazole | Between group difference * (95% CI) |
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|
No. of MITT patients | 127 | 118 | |
Global Success (MITT) At End Of IV Therapy |
| | | |
Candidemia | 88/116 (75.9%) | 63/103 (61.2%) | 14.7 (2.5, 26.9) |
Neutropenic
| 1/2 | 2/4 | - |
Non neutropenic | 87/114 (76.3%) | 61/99 (61.6%) | - |
| | | |
Multiple sites | | | |
Peritoneal fluid/ intra-abdominal abscess | 4/6 | 5/6 | - |
Blood/ peritoneum (intra-abdominal abscess) | 2/2 | 0/2 | - |
Blood /bile | - | 1/1 | - |
Blood/renal | - | 1/1 | - |
Pancreas | - | 0/3 | - |
Pelvic abscess | - | 1/2 | - |
Pleural fluid | 1/1 | - | - |
Blood/ pleural fluid | 0/1 | - | - |
Blood/left thigh lesion biopsy | 1/1 | - | - |
Total | 8/11 (72.7%) | 8/15 (53.3%) | - |
Mortality |
Overall study mortality | 29/127 (22.8 %) | 37/118 (31.4%) | - |
Mortality during study therapy | 10/127 (7.9%) | 17/118 (14.4%) | - |
Mortality attributed to Candida | 2/127 (1.6%) | 5/118 (4.2%) | - |
Pediatric Candidemia/Invasive Candidiasis Trial
A prospective, open-label, non-comparative, multinational trial (National Clinical Trial (NCT) number 00761267) assessed the safety and efficacy of ERAXIS in 68 pediatric patients aged 1 month to <18 years with candidemia/invasive candidiasis. Patients were stratified by age (1 month to <2 years, 2 to <5 years, and 5 to <18 years) and received once daily intravenous ERAXIS (3 mg/kg loading dose on Day 1, and 1.5 mg/kg daily maintenance dose thereafter) followed by an optional switch to oral fluconazole (6–12 mg/kg/day, maximum 800 mg/day) up to Day 49. Patients were followed at 2 and 6 weeks after EOT.
Among 68 ERAXIS-treated patients, 64 had microbiologically confirmed Candida infection and were evaluated for efficacy in the modified intent-to-treat (MITT) population. Overall, 59 patients (92.2%) had Candida isolated from blood only. The most commonly isolated pathogens were Candida albicans (25 [39.1%] patients), followed by Candida parapsilosis (17 [26.6%] patients), and Candida tropicalis (9 [14.1%] patients). A successful global response was defined as having both successful clinical (cure or improvement) and microbiological (eradication or presumed eradication) response. The overall rates of successful global response in the MITT population are presented in Table 12 below.
Table 12: Summary of Successful Global Response by Age Group, MITT Population | Successful Global Response, n (%) |
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Timepoint | Global Response | 1 month to <2 years (N = 16) n (n/N, %) | 2 to <5 years (N=18) n (n/N, %) | 5 to <18 years (N=30) n (n/N, %) | Overall (N=64) n (n/N, %) |
---|
95% CI = exact 95% confidence interval for binomial proportions using Clopper-Pearson method; EOIVT = end of intravenous treatment; EOT = end of treatment; FU = follow-up; MITT = modified intent-to-treat; N = number of subjects in the population; n = number of subjects with responses. |
EOIVT | Success | 11 (68.8) | 14 (77.8) | 20 (66.7) | 45 (70.3) |
-
- 95% CI
| (41.3, 89.0) | (52.4, 93.6) | (47.2, 82.7) | (57.6, 81.1) |
EOT | Success | 11 (68.8) | 14 (77.8) | 21 (70.0) | 46 (71.9) |
-
- 95% CI
| (41.3, 89.0) | (52.4, 93.6) | (50.6, 85.3) | (59.2, 82.4) |
2-week FU | Success | 11 (68.8) | 13 (72.2) | 22 (73.3) | 46 (71.9) |
-
- 95% CI
| (41.3, 89.0) | (46.5, 90.3) | (54.1, 87.7) | (59.2, 82.4) |
6-week FU | Success | 11 (68.8) | 12 (66.7) | 20 (66.7) | 43 (67.2) |
-
- 95% CI
| (41.3, 89.0) | (41.0, 86.7) | (47.2, 82.7) | (54.3, 78.4) |