PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME/INN: Vfend / Voriconazole. THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI PROTOCOL NO.: 150-608 PROTOCOL TITLE: A randomized, open label, comparative multicenter study of voriconazole versus conventional amphotericin B fluconazole in the treatment of candidemia in non neutropenic subjects Study Center(s): This study was conducted at 103 centers in 28 countries (Argentina [2 centers], Australia [2], Austria [1], Belgium [5], Brazil [5], Canada [4], Czech Republic [1], France [3], Germany [3], Hong Kong [2], India [10], Israel [3], Malaysia [1], Mexico [2], Morocco [2], the Netherlands [1], Panama [1], the Philippines [3], Poland [2], the Slovak Republic [1], South Africa [5], South Korea [4], Spain [6], Switzerland [3], Taiwan [1], Thailand [2], the United Kingdom [1] and the United States [27]). Study Initiation and Completion Dates: 10 September 1998 to 05 May 2003 Phase of Development: Phase 3 Study Objective(s): The primary objective of this study was to compare the efficacy and safety of voriconazole and conventional amphotericin B fluconazole in the treatment of candidemia in non-neutropenic subjects. The secondary objectives were to examine health care resources utilization in subjects treated with voriconazole and conventional amphotericin B and to examine the population pharmacokinetics of voriconazole. Health care resource and pharmacokinetic data are discussed in separate reports. METHODS Study Design: This was a randomized, open, comparative multicenter study. Subjects received either voriconazole or amphotericin B fluconazole. Subjects received intravenous (iv) treatment for at least the first three days then they could switch to oral therapy. Subjects were treated for at least 14 days after candidemia resolution up to a maximum of eight weeks. Investigators assessed clinical response at end of therapy (EOT) and at 2, 6 and 12 weeks after EOT. Subjects were assessed for safety, including visual safety testing, throughout the study. Subjects who were considered to be at risk of cardiac arrhythmia were required to be continuously monitored during IV therapy. Number of Patients (planned and analyzed): Planned: Four hundred and twenty-six (426) subjects were to be randomized to achieve 360 eligible subjects for inclusion in the MITT efficacy analysis.
Analyzed: Four hundred and three (403) subjects were analyzed. Diagnosis and Main Criteria for Inclusion: Males or non pregnant females, aged 12 years old or older, with at least one positive blood culture isolation of Candida spp. from a blood sample taken within 96 hours prior to randomization. Subjects who have clinical evidence of infection at some time within 48 hours prior to enrollment, including at least one of the following: Temperature >100 F (37.8 C) on two occasions at least four hours apart or one determination >101.5 F (38.6 C), Systolic blood pressure <90, or a >30mmHg decrease in systolic blood pressure from the subject's normal baseline and, Signs of inflammation (swelling, heat, erythema, purulent drainage) from a site infected with Candida (e.g., joint, skin, eye, bone, esophagus). Study Treatment: Voriconazole for IV injection as a lyophilized powder was supplied in 25 ml vials (either 10 mg/ml or 200 mg iv vials). Intravenous administration was 6 mg/kg loading dose every 12 hours for 24 hours then 3 mg/kg every 12 hours. Voriconazole 50 mg and 200 mg tablets were used for oral administration. The oral dose was 200 mg bid but this could be reduced to 100 mg bid for subjects weighing < 40kg and escalated to 300 mg bid or to 150 mg for subjects weighing < 40kg. Amphotericin B (supplied in 50 mg IV vials) was given at a dose of at least 0.7 mg/kg IV, daily. Fluconazole (supplied as 50 mg, 100 mg and 200 mg capsules, 100 mg, 200 mg and 400 mg iv vials and a 50 mg/5 ml oral suspension) was given at a dose of 400 mg oral or IV daily. Subjects received either voriconazole or amphotericin B fluconazole. Subjects received IV treatment for three days then could switch to oral therapy. Subjects who did not tolerate amphotericin B could switch to fluconazole after less than three days. Subjects were treated for at least 14 days after candidemia resolution. Subjects received a maximum of eight weeks treatment. Efficacy Evaluations: Investigator and Data Review Committee (DRC) assessed response to treatment. In addition, time to death, mycology, eye assessments and vital signs were recorded. Pharmacokinetic Evaluations: Voriconazole plasma concentrations were obtained from blood samples collected weekly up to EOT. Protocol 150-608 / Page 2 of 12
Safety Evaluations: Safety evaluations included adverse events, serious adverse events, laboratory safety tests, visual assessments and cardiac monitoring. Statistical Methods: There were three defined subject populations comprising two efficacy populations [modified intent to treat (MITT) and per protocol (PP)], and one Safety population. Primary Objective: To test the hypothesis that voriconazole is not inferior to amphotericin B fluconazole, voriconazole would be considered non-inferior if the lower limit of the 95% confidence interval (CI) around the difference in success rates between the two groups did not fall below 15% for the MITT population. The primary endpoint of DRC success rate 12 weeks after EOT was derived from the DRC s assessment of response to antifungal therapy. Success rates and differences in success rates with 95% CIs were calculated and stratified by region. Secondary Objectives: The DRC made a single assessment of response at the latest most relevant time point at EOT, 2, 6 or 12 weeks after EOT. The success rates and the difference in success rates between the two treatment groups were analyzed. The effect of six pre-specified cofactors (predisposing factor to candidemia, age, race, site of infection, catheter removal and US/non-US sites) on the primary analysis was examined. The investigator assessment of response at EOT and the comparison between the investigator and the DRC assessments were analyzed. Death: The Kaplan Meier product limit estimator was used to plot the cumulative death rate over time for the two efficacy populations and then the Cox s proportional hazards model was used to statistically analyze the data, with region as a covariate, to estimate the hazard ratio, with 95% CIs between the two treatment groups. RESULTS Subject Disposition and Demography: There were 433 subjects screened from all centers. Six subjects from one center were excluded from all analyses because the data were found to be unreliable. Therefore, in total, 427 subjects were screened, 422 were randomized (283 to voriconazole and 139 to amphotericin B fluconazole) and 403 (272 to voriconazole and 131 to amphotericin B fluconazole) were treated. A total of 122 subjects (45%) in the voriconazole group and 59 subjects (45%) in the amphotericin B fluconazole group completed the study. The demographic profile was similar for each population of each treatment group. There were 233 males (58%) and 170 females (42%). The mean age was 53.5 ranging from 13 to 90. There were 228 white subjects (57%), 65 black subjects (16%), 88 Asian subjects (22%) and 22 subjects of other races (5%). Protocol 150-608 / Page 3 of 12
Efficacy Results: Primary Endpoint: DRC Response Assessment 12 Weeks after EOT: The results from the primary analysis in the MITT population showed that voriconazole is non-inferior to amphotericin B fluconazole. The stratified difference in success rates 12 weeks after EOT was 0.04% (95% CI; -10.55% to 10.63%), with the lower limit within the pre-specified 15% non-inferiority margin. Table S1 shows the number and % of subjects that the DRC assessed as cured or improved 12 weeks after EOT, and the number and % who were not in either category. Table S1 DRC Response Assessment 12 Weeks after End of Therapy (MITT population) No. (%) of Subjects Voriconazole N=248 Amphotericin B fluconazole N=122 Cured 101 (41%) 49 (40%) Improved 0 1 (1%) Not Cured/Improved 147 (59%) 72 (59%) The stratified success rate was 40.72% (95% CI: 34.61, 46.84) and 40.70% (95% CI: 32.06, 49.35) in the voriconazole and amphotericin B fluconazole groups, respectively. The unstratified success rates were very similar to the stratified success rates. The results from the primary analysis in per protocol population were consistent with those in the MITT population. Secondary Endpoint: DRC Response Assessment EOT or 2 or 6 or 12 Weeks after EOT: In the MITT population, the stratified success rate was 65.48% and 71.33% in the voriconazole and amphotericin B fluconazole groups, respectively, with the stratified difference in success rates being -5.80% (95% CI; -15.77% to 4.16%). Similar results were seen for the unstratified success rate (MITT population) and for both the stratified and unstratified success rates in the per protocol population. A contributing factor to the lower response in the voriconazole group was the higher rate of study drug discontinuations due to adverse events reported in the voriconazole group than in the amphotericin B fluconazole group. Subjects who switched treatment from amphotericin B to fluconazole because of toxicity were not counted as treatment discontinuations. Table S2 shows the distribution of the timing of the DRC assessments for the MITT population Protocol 150-608 / Page 4 of 12
Table S2 DRC Response Assessment at End of Therapy and 2, 6 or 12 Weeks after End of Therapy (MITT population) Voriconazole N=248 Amphotericin B fluconazole N=122 End of Therapy Improved 35 (14%) 24 (20%) Failed 65 (26%) 26 (21%) Indeterminate 3 (1%) 2 (2%) Withdrawn 7 (3%) 4 (3%) 2 weeks after End of Improved 2 (1%) 0 Therapy Cured 16 (7%) 7 (6%) Relapsed 8 (3%) 2 (2%) 6 weeks after End of Improved 0 0 Therapy Cured 8 (3%) 6 (5%) Relapsed 2 (1%) 1 (1%) 12 weeks after End of Improved 0 1 (1%) Therapy Cured 101 (41%) 49 (40%) Relapsed 1 (<0.5%) 0 The results for the per protocol population were similar to those for the MITT population. Table S3 shows, for the MITT population of both treatment groups, the reasons for DRC assessment of failure at EOT. Table S3 Reasons for Failure at EOT (MITT population) No of Subjects Voriconazole (N=248) Amphotericin B fluconazole (N=122) Failed at EOT a 65 (26%) 26 (21%) Blood cultures did not become negative 28 (43%) 12 (46%) Study drug stopped for toxicity b 22 (34%) 5 (19%) Additional antifungal treatment required 42 (65%) 12 (46%) Other c 19 (29%) 10 (38%) a Subjects may have had >1 reason for failure at EOT; b All of these subjects had additional antifungals; c 89% of subjects who had this category as the only reason for failure died on the day of EOT or within 24 hours of EOT. Death as an Efficacy Measure Time to Death: In the MITT population 88/248 (35.5%) and 51/122 (41.8%) subjects had died by Day 98 in the voriconazole and amphotericin B fluconazole groups, respectively. The probability of death 98 days after randomization was 0.364 and 0.423 in the voriconazole and amphotericin B fluconazole groups, respectively. The difference in survival rates was not statistically significant; hazard ratio of 0.822 (95% CI: 0.582 to 1.161) in favor of voriconazole. The mean APACHE II scores at baseline were comparable for both treatment groups, and the survival rates for this study were similar to those reported in other studies of candidemia. When considering age as an explanatory variable, an interaction between age and treatment group was observed (p=0.0572). In the 65 year age group, subjects receiving voriconazole had a better survival profile, whilst in the >65 year age group, subjects receiving amphotericin B fluconazole had a better survival profile. On examination of the baseline measurements for each Protocol 150-608 / Page 5 of 12
group, most variables were distributed similarly across the treatment groups within age groups. The one major exception was staying in an ICU at baseline. There were more voriconazole subjects aged >65 years in an ICU than for amphotericin B fluconazole, and more amphotericin B fluconazole subjects aged 65 years in an ICU than for voriconazole subjects. The age by drug interaction was no longer significant when staying in an ICU at baseline was included in the model. The co-factor US vs non-us also significantly affected survival (p=0.0056). The US subjects had better survival than non-us subjects in both treatment groups. None of the other co-factors defined had a significant effect on survival. The assumption of proportional hazards was considered adequate for all analyses. Contribution of Candidemia to Death: The DRC assessed that candidemia was probably contributory to death in 27/248 subjects (11%) and 14/122 subjects (12%) in the voriconazole and amphotericin B fluconazole groups, respectively. With the exception of one subject in each group, candidemia was considered by the DRC to probably not be contributory in all of the other deaths. Primary Endpoint Adjusted for Other Factors: In an exploratory analysis of the primary endpoint, six pre-specified co-factors (predisposing factor to candidemia, age, race, site of infection, catheter removal and US/non-US sites) were tested for an effect on the primary response variable. Only the predisposing factor to candidemia demonstrated an interaction with treatment (p=0.0591) where subjects in the non-abdominal surgery group receiving amphotericin B fluconazole had a higher response rate than in the other groups. There were a relatively low number of subjects (voriconazole N=32 and amphotericin B fluconazole N=15) who were in the predisposing factor to candidemia non-abdominal surgery group. None of the other six prespecified co-factors had a statistically significant effect on the primary endpoint. Investigator Response Assessment: The investigator assessment of response was similar for both treatment groups at all four time points (Table S4). Table S4 Number and Percentage % of Subjects with a Successful Outcome as Assessed by the Investigator (MITT population) Time point Voriconazole (N=248) Amphotericin B fluconazole (N=122) EOT 178 (72%) 88 (72%) 2 weeks after EOT 125 (50%) 62 (51%) 6 weeks after EOT 104 (42%) 55 (45%) 12 weeks after EOT 104 (42%) 51 (42%) EOT=end of therapy. Investigator and DRC Response Assessment Comparison: There were differences in the method of response assessments made by investigators and the DRC. The DRC made a single assessment of response to treatment at a variable time point, whereas the investigators made an assessments at four fixed time points, EOT, 2, 6 and 12 weeks after EOT. For example, investigators assessed Protocol 150-608 / Page 6 of 12
fifteen voriconazole subjects as improved at EOT whom the DRC assessed as failed (9), indeterminate (1) and withdrew (5). Investigators assessed 2 amphotericin B fluconazole subjects as improved at EOT whom the DRC assessed as withdrew (2). Funduscopy: At baseline the number of subjects assessed as having an abnormal fundus related to candidiasis, was seven and five subjects for the left eye and eight and four subjects, for the right eye in the voriconazole and amphotericin B fluconazole groups, respectively. At six weeks after EOT, in both the left and right eyes two and zero subjects, respectively, were assessed as having an abnormal fundus related to candidiasis. None of the subjects with an abnormal fundus related to candidiasis at baseline was assessed as having an abnormal fundus related to candidiasis six weeks after EOT. Mycology: Table S5 presents the response rates by baseline pathogen type. Table S5 Number and Percentage of Subjects with a Successful Outcome 12 weeks after EOT, by Baseline Pathogen Type No of Subjects a Voriconazole (N=248) Amphotericin B fluconazole (N=122) Candida albicans 46/107 (43%) 30/63 (48%) Candida non-albicans 58/150 (39%) 20/61 (33%) C. glabrata 12/36 (33%) 7/21 (33%) C. krusei 1/4 (25%) 0/1 C. parapsilosis 24/45 (53%) 10/19 (53%) C. tropicalis 17/53 (32%) 1/16 (6%) a Subjects could have >1 baseline pathogen. The success rates 12 weeks after EOT were similar in the two treatment groups, for each Candida species except C. tropicalis where voriconazole subjects had a higher response rate than amphotericin B fluconazole subjects. Time to Negative Blood Cultures: In both treatment groups, the median time to first negative blood culture was two days. DRC Assessed Failures: A response category of success was defined as those subjects who were improved at EOT and those that were cured or improved at 2, 6 and 12 weeks after EOT. A response category of failure was defined as either subjects who were assessed as failure at EOT by the DRC or those that were assessed as indeterminate, withdrawn and relapsed after EOT. There were 121 subjects scored neither as cured nor improved by the DRC. The majority of these non-successful subjects who were failures at EOT (Table S6). Protocol 150-608 / Page 7 of 12
Table S6 DRC Assessed Failures at End of Therapy Voriconazole Amphotericin B fluconazole N=122 N=248 DRC successful response (cured or improved) 162 (65.3%) 87 (71.3%) DRC non-successful responses All 86 (34.7%) 35 (28.7%) Failure at EOT a 65 (26.2%) 26 (21.3%) Other non-successful outcomes 21 (8.5%) 9 (7.4%) Indeterminate 3(1.2%) 2 (1.6%) Withdrawn 7 (2.8%) 4(3.3%) Relapse 11 (4.4%) 3 (2.5%) a A subject may have had more than one reasons for failure. Reasons for failure are given in Table S3. Sixty-five (26%) voriconazole treated subjects and 26 (21%) amphotericin B fluconazole subjects failed at EOT. The proportion for which at least one reason for failure was failure to clear the bloodstream was similar in both groups. Those who failed for other reasons were also similarly distributed between the two treatment groups. There were a disproportionately greater number of subjects with study drug stopped for toxicity and additional antifungals required in the voriconazole group compared with the amphotericin B fluconazole group. The time to failure at the primary endpoint was similar in both groups throughout the period of treatment and up to 12 weeks after EOT. For the primary endpoint any subject not scored as a success at the 12 weeks after EOT was considered a failure. Therefore, in addition to the DRC-assessed failures discussed above, those subjects who were not available for the 12 weeks after EOT visit, who died or were lost to follow-up, or whose assessment was censored by the DRC at an earlier time point, were added to the failure category in the primary analysis. Death before the 12 weeks after EOT assessment was the predominant reason why DRC-scored successes were converted to failures within the primary analysis. A greater proportion of amphotericin B fluconazole subjects scored as successes by the DRC died before 12 weeks after EOT: 27 of 87 (31%) compared with 36 of 162 (22%) in the voriconazole group. All of the deaths were considered unrelated to the Candida infection. Of the remaining 35 subjects with an outcome censored as success by the DRC, 31 subjects were known to be living 12 weeks after EOT or Day 98; survival status was not known for four subjects. The DRC censored assessments were due to missing 12 weeks after EOT data or to the administration of other systemic antifungals. Table S7 below shows the successes censored before 12 weeks after EOT. Protocol 150-608 / Page 8 of 12
Table S7 Number and Percentage of Subjects with DRC Censored Assessments Distribution of subjects at primary and secondary endpoints Voriconazole (N=248) Amphotericin B fluconazole (N=122) DRC success (secondary endpoint) 162 (65.3%) 87 (71.3%) Success at 12 weeks after EOT (primary endpoint) 101 (40.7%) 50 (41.0$) Difference (DRC successes who became failures at 12 61 (24.6%) 37 (30.3%) weeks after EOT) Reasons for failure at 12 weeks after EOT Died before 12 weeks after EOT 36 (14.5%) 27 (22.1%) Alive 22 (8.9%) 9 (7.4%) Survival status not known 3 (1.2%) 1 (0.8%) Surviving a DRC-censored successes 25 (10.1%) 10 (8.2%) Lost to follow-up, withdrew consent 12 (4.8%) 2 (1.6%) Prophylaxis 1 (0.4%) 2 (1.6%) Other unrelated or new fungal infection 6 (2.4%) 2 (1.6%) Miscellaneous reason 3 (1.2%) 4 (3.3%) >1 of the reasons above or use of other systemic 3 (1.2%) 0 antifungal a Includes four subjects whose survival status was not known. Although there were a disproportionately larger number of voriconazole subjects who were lost to follow-up, it was known that at least nine of the 12 (75.0%) were alive at Day 98. Secondary Endpoint: DRC Response Assessment EOT or 2 or 6 or 12 Weeks after EOT. Sensitivity analysis: Subjects who were assessed as a success by the DRC at an earlier time point than 12 weeks after EOT and died within seven days of EOT were set to failure. In the MITT population, the stratified difference in success rates was -2.62% (95% CI; -13.16 to 7.92%). The stratified success rate was 59.68% and 62.35% in the voriconazole and amphotericin B fluconazole groups, respectively. The difference in the treatment groups in this sensitivity analysis was smaller than in the original secondary analysis (-5.99%). Pharmacokinetic Results: Pharmacokinetic results are included in a separate report. Safety Results: Nearly every subject in this study had at least one adverse event. The pattern of adverse events was similar in the two groups but the frequency of those that occurred for >5% in either group, tended to be higher in the amphotericin B fluconazole group. Table S8 lists all adverse events reported in 10% of the subjects in either group, by body system. Protocol 150-608 / Page 9 of 12
Table S8 Treatment Emergent Adverse Events Reported in 10% Subjects in Either Treatment Group No of Subjects Voriconazole Amphotericin B fluconazole Treated 272 131 With 1 adverse event 266 (97.8%) 130 (99.2%) Body as a whole Fever 41 (15.1%) 24 (18.3%) Sepsis 57 (21.0%) 33 (25.2%) Cardiovascular Hypotension 33 (12.1%) 27 (20.6%) Digestive Vomiting 24 (8.8%) 17 (13.0%) Hemic and lymphatic Anemia 32 (11.8%) 16 (12.2%) Metabolic and nutritional Alkaline phosphatase 28 (10.3%) 10 (7.6%) Creatinine 2 (0.7%) 14 (10.7%) Hypokalemia 33 (12.1%) 29 (22.1%) Peripheral edema 28 (10.3%) 12 (9.2%) Respiratory Respiratory disorder 31 (11.4%) 19 (14.5%) Urogenital Acute kidney failure 20 (7.4%) 14 (10.7%) Urinary tract infection 30 (11.0%) 14 (10.7%) The most common adverse event was sepsis, followed by hypotension, fever, hypokalemia and respiratory disorder. A higher proportion of subjects in the amphotericin B fluconazole group had renal adverse events whereas a similar proportion of subjects in either group had hepatic adverse events. Most adverse events in both groups were mild or moderate. A total of 137 (50%) and 74 (57%) subjects had a severe adverse event in the voriconazole and the amphotericin B fluconazole groups, respectively. The incidence of the adverse events that had led to discontinuation was similar between the two treatment groups. Table S9 gives the incidence of the most common adverse events that led to discontinuation. Table S9 Most Frequently Reported Adverse Events Leading To Discontinuation No of Subjects Voriconazole (N=272) Amphotericin B fluconazole (N=131) Sepsis 57 (21.0%) 33 (25%) Alkaline phosphatase 28 (10.3%) 10 (8%) Acute kidney failure 20 (7.4%) 14 (11%) Heart arrest 20 (7.4%) 10 (8%) Rash 16 (5.9%) 7 (5%) AST 14 (5.1%) 4 (3%) ALT 9 (3.3%) 6 (5%) Approximately a third of the voriconazole subjects had at least one treatment-related adverse event compared to approximately a half of the amphotericin B fluconazole subjects. Most Protocol 150-608 / Page 10 of 12
treatment-related adverse events were mild or moderate. Only hypokalemia, acute kidney failure, abnormal kidney function, increased creatinine and chills were considered to be treatment related in more than 5% of subjects and these all occurred at higher frequency in the amphotericin B fluconazole group. The proportion of subjects with a severe treatment related adverse event was approximately 10% in both groups. In the safety population 98 (36.0%) and 55 (42.0%) subjects had died by Day 98 in the voriconazole and amphotericin B fluconazole groups, respectively. The probability of death 98 days after randomization was 0.364 and 0.423, respectively. The difference in survival rates was not statistically significant; hazard ratio of 0.826 (95% CI: 0.593 to 1.149) in favor of voriconazole. The most common reasons for death were as expected for such a critically ill population and included sepsis or sepsis shock; multiple-organ failure; cardiac or respiratory arrest and respiratory failure. There were 128 (32%) subjects who died during the study or within 30 days after EOT, 82 of the voriconazole group (30%) and 46 (35%) of the amphotericin B fluconazole group. A total of 175 (64%) subjects in the voriconazole group and 106 (81%) subjects in the amphotericin B fluconazole group had at least one serious adverse event. Table S10 shows serious adverse events reported in more than 5% of the subjects in either group. Table S10 Serious Adverse Events Reported in > 5% of Subjects In Either Group No of Subjects Voriconazole (N=272) Amphotericin B fluconazole (N=131) With 1 adverse event 175 (64%) 106 (81%) Sepsis (not otherwise specified) 32 (12%) 20 (15%) Respiratory failure 26 (10%) 16 (12%) Cardiac arrest 21 (8%) 12 (9%) Hypotension (not otherwise specified) 16 (6%) 11 (8%) Cardio-respiratory arrest 14 (5%) 8 (6%) Multi-organ failure 9 (3%) 11 (8%) Septic shock 13 (5%) 6 (5%) Acute renal failure 11 (4%) 7 (5%) The most common serious adverse events were sepsis, respiratory failure, cardiac arrest, hypotension and cardio-respiratory arrest. Most of these events were due to the disease under study or underlying disease. There were no clinically significant differences in the median changes in hematological or hepatic parameters. There were no clinically significant changes in standing or supine systolic or diastolic blood pressure, pulse rate or temperature in either study drug group. Over three quarters of subjects did not have a visual acuity test. Of those that did have enough information to assess baseline to EOT changes there were 24 (9%) and four (3%) subjects with Protocol 150-608 / Page 11 of 12
visual acuity deterioration in the voriconazole and amphotericin B fluconazole groups, respectively. At six weeks after EOT the deterioration had resolved or had some improvement in seven and one subjects in the voriconazole and amphotericin B fluconazole group, respectively. One subject in each group had a further deterioration whilst for all other subjects the deterioration remained stable. There was no evidence of significant visual field changes or permanently significant funduscopy changes. CONCLUSION(S): Voriconazole was as effective as the regimen of amphotericin B fluconazole, in both C. albicans and non-albicans candidemia. The safety profile of the two treatment groups was similar apart from a higher frequency of renal events in the amphotericin B fluconazole group. Based on a report completed on: 20 February 2004 Protocol 150-608 / Page 12 of 12