14 CLINICAL STUDIES
14.1 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 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 7.
|n (%)||n (%)|
|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 8.
|Treatment Difference*, % (95% C.I.)|
|End of IV Therapy||96 (75.6)||71 (60.2)||15.4|
|End of All Therapy†||94 (74.0)||67 (56.8)||17.2|
|2 Week Follow-up||82 (64.6)||58 (49.2)||15.4|
|6 Week Follow-up||71 (55.9)||52 (44.1)||11.8|
Table 9 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.
|ERAXIS||Fluconazole||Between group difference *|
|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)|
|Non neutropenic||87/114 (76.3%)||61/99 (61.6%)||-|
|Peritoneal fluid/ intra-abdominal abscess||4/6||5/6||-|
|Blood/ peritoneum (intra-abdominal abscess)||2/2||0/2||-|
|Blood/ pleural fluid||0/1||-||-|
|Blood/left thigh lesion biopsy||1/1||-||-|
|Total||8/11 (72.7%)||8/15 (53.3%)||-|
|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%)||-|
14.2 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 ERAXIS-treated patients, the age range was 16–69 years, the gender distribution was 42% male and 58% female, and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races.
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.
Efficacy was assessed by 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 10). 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 10).
|Endoscopic Response at End of Therapy|
|Treatment Difference*||95% CI|
|Endoscopic Success, n (%)||225 (97.4)||233 (98.7)||-1.3%||-3.8%, 1.2%|
|Cure||204 (88.3)||221 (93.6)|
|Improvement||21 (9.1)||12 (5.1)|
|Failure, n (%)||6 (2.6)||3 (1.3)|
|Endoscopic Relapse Rates at Follow-Up, 2 Weeks Post-Treatment|
|ERAXIS||Fluconazole||Treatment Difference*||95% CI|
|Endoscopic Relapse, n/N (%)||120/225 (53.3%)||45/233 (19.3%)||34.0%||25.8%, 42.3%|
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.