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A Randomized, Double-Blind Trialof Anidulafungin versus Fluconazolefor the Treatment of Esophageal Candidiasis David S. Krause,1 A. E. Simjee,3 Christo van Rensburg,4 Johann Viljoen,5 Thomas J. Walsh,2 Beth P. Goldstein,1
Michele Wible,1 and Timothy Henkel1
1Vicuron Pharmaceuticals, King of Prussia, Pennsylvania; 2Infectious Diseases Section, National Cancer Institute, Bethesda, Maryland;and 3Nelson R. Mandela School of Medicine and King Edward VIII Hospital, Durban, 4Tigerberg Hospital, Cape Town, and 5Bloemfontein,Republic of South Africa (See the editorial commentary by Darouiche on pages 850–2 and the article by de Wet et al. on pages 842–9)
Anidulafungin is a novel antifungal agent of the echinocandin class. This randomized, double-blind, double-
dummy study compared the efficacy and safety of intravenous anidulafungin to that of oral fluconazole in
601 patients with endoscopically and microbiologically documented esophageal candidiasis. Patients received
intravenous anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day
1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14–21 days). At the end of
therapy, the rate of endoscopic success for anidulafungin (242 [97.2%] of 249 treated patients) was found to
be statistically noninferior to that for fluconazole (252 [98.8%] of 255 treated patients; treatment difference,
Ϫ1.6%; 95% confidence interval, Ϫ4.1 to 0.8). The safety profile of anidulafungin was similar to that of
fluconazole; treatment-related adverse events occurred in 9.3% and 12.0% of patients, respectively. Laboratory
parameters were similar between treatment arms. Anidulafungin is as safe and effective as oral fluconazole
for the treatment of esophageal candidiasis, when assessed at the completion of therapy.
The rate of fungal infections has increased in recent responsible for incapacitating illness [2]. Esophageal decades for a number of reasons: acquired immuno- candidiasis may be asymptomatic or may cause sub- suppression associated with HIV infection, iatrogenic stantial morbidity and discomfort and serve as a focus immunosuppression caused by treatment of cancer and of invasive disease. It may arise as a contiguous exten- the prevention of transplanted-organ rejection, wide- sion of oropharyngeal infection, or it may arise de novo, spread use of broad-spectrum antibiotics and cortico- without concomitant thrush [3]. Candida albicans is steroids, and use of increasingly invasive surgical tech- the most often implicated species in esophageal can- niques and technologies in compromised hosts.
didiasis; it consistently accounts for у90% of baseline Mucocutaneous candidiasis may be the first sign of HIV isolates [3–7]. Because patients may have inability to infection. In individuals with advanced HIV disease, swallow, parenteral therapy may be required [4].
esophageal candidiasis, which is characterized by odyn- Prompt therapy with a systemic agent is indicated ophagia, dysphagia, and retrosternal chest pain, is as [4]. Unfortunately, almost all patients with AIDS and common as oropharyngeal candidiasis [1] and may be successfully treated esophageal candidiasis will developa recurrence in the absence of immune reconstitution,usually within 2–3 months [8]. Therefore, chronic sup- Received 9 December 2003; accepted 11 March 2004; electronically published pressive prophylaxis or intermittent therapy is the cur- Reprints or correspondence: David S. Krause, Vicuron Pharmaceuticals, 455 S.
rent standard of care after an initial course of treatment Gulph Rd., Ste. 310, King of Prussia, PA 19406 ([email protected]).
Clinical Infectious Diseases
2004; 39:770–5
Anidulafungin, an echinocandin, is a novel drug in ᮊ 2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3906-0003$15.00 development for the treatment of fungal infections.
770 • CID 2004:39 (15 September) • Krause et al.
Members of this class are noncompetitive inhibitors of (1,3)- study. Other major exclusion criteria were receipt of systemic beta-d-glucan synthase, an enzyme required for the synthesis antifungals in the week before study enrollment, a life expec- of glucan (the polysaccharide that constitutes the major portion tancy of !2 months, serum aminotransferase or total serum of the cell wall of many pathogenic fungi). Glucan synthase is bilirubin levels of 13 times the upper limit of the normal range, not found in mammalian cells and thus represents an ideal a serum creatinine level of 12.5 times the upper limit of the target for antifungal agents. Consistent with its mechanism of normal range, an absolute neutrophil count of !500 neutro- action (interference with cell wall synthesis), anidulafungin is phils/mm3, or a platelet count of !60,000 platelets/mm3.
fungicidal for Candida species [10, 11]. The spectrum of activity Study design and treatment.
of anidulafungin includes Candida (all species tested, including randomized, double-blind, double-dummy, noninferiority those strains that are resistant to fluconazole and amphotericin) study. Patients were randomized either to receive intravenous and Aspergillus species [11–19]. When administered parenter- anidulafungin (a 100-mg loading dose on day 1, followed by ally, anidulafungin is highly efficacious in animal models of 50 mg q.d.) and oral placebo (given daily) or to receive intra- esophageal and disseminated candidiasis, including immuno- venous placebo (given daily; i.e., anidulafungin vehicle without suppressed and immunocompetent mice and rabbits [20–23].
active drug) and oral fluconazole (a 200-mg loading dose on Clinical studies have shown that the half-life of anidulafungin day 1, followed by 100 mg q.d.). Intravenous loading and daily is ∼1 day and reflects slow chemical degradation [24]. The same maintenance doses were administered over 90- and 45-min slow chemical degradation occurs in vitro at physiologic pH periods, respectively. Therapy was to be continued for 7 days and temperatures. Anidulafungin is not metabolized by the after resolution of symptoms but not for !14 or 121 days in liver, is not eliminated in the urine, and is not a substrate, inhibitor, or inducer of the enzymes in the cytochrome P450 Endoscopic, clinical and mycological assessments (including system. No dosage adjustments appear to be required based on culture and speciation of Candida isolates) were performed at sex, weight, age, ethnicity, or disease status or for patients with baseline, at end of therapy, and at a follow-up visit that occurred any degree of hepatic or renal insufficiency or who are receiving 2 weeks after the end of treatment. In the event of clinical concomitant medications [25]. In a phase 2 dose-ranging study, recurrence, the follow-up assessment was conducted earlier.
anidulafungin was well tolerated and efficacious in patients with Endoscopic appearance of the esophageal mucosa was graded invasive candidiasis [26]. The present study was conducted to as follows: 0, normal esophageal mucosa; 1, individual plaques, compare the efficacy and safety of intravenous anidulafungin each р2 mm in diameter; 2, individual plaques 12 mm in (50 mg q.d.) with that of oral fluconazole (100 mg q.d.) for diameter; or 3, confluent plaques and/or increased friability of the treatment of patients with esophageal candidiasis.
mucosa [27]. The severity of odynophagia and/or dysphagiaand retrosternal pain was assessed daily and classified as absent, mild, moderate, or severe. Investigator sites were provided with Patients.
This study was conducted in accordance with the standard definitions of symptoms. For example, mild dysphagia Declaration of Helsinki (1996), the International Conference was defined as “discomfort on swallowing solids but little dis- on Harmonization Guideline for Good Clinical Practice (2000), comfort on swallowing liquids.” At screening, presumptive mi- and applicable local regulations. An independent ethics com- croscopic diagnosis of Candida infection was made by dem- mittee or institutional review board for each site approved the onstration of yeast and/or hyphal forms in brushings or biopsies study, and written informed consent was obtained from each of plaque smears or exudates using Gram, periodic acid-Schiff, or silver staining. In addition, endoscopic material was obtained Male or female patients (age, 18–65 years) who had esoph- for culture for identification and susceptibility testing. Candida ageal candidiasis diagnosed and who had a predisposing risk isolates were sent to a central laboratory for speciation and factor for fungal infection (including antibiotic, corticosteroid, determination of antifungal MICs (M. Pfaller; University of or radiation therapy; myelosuppression; malnutrition; or AIDS) were eligible for the study. The diagnosis of esophageal can- Efficacy analyses.
didiasis was based on endoscopic findings, clinical symptoms analysis of efficacy was a comparison of endoscopic response in (odynophagia, dysphagia, and/or retrosternal pain), biopsy ex- evaluable (per-protocol) patients at the end of therapy. Endo- clusion of herpes simplex virus and cytomegalovirus infection, scopic response was scored as a success if patients had complete and mycological findings (isolation of Candida species and/or resolution of esophageal lesions (i.e., cure; grade 0) or a decrease of у1 grade from the baseline level (i.e., improvement).
Patients with evidence of systemic fungal infection, ulcerative Secondary efficacy analyses included clinical response (a suc- esophageal lesions, or known hypersensitivity to anidulafungin, cessful response was defined as the absence or improvement its excipients, or other echinocandins were excluded from the of symptoms, compared with baseline) and mycological re- Anidulafungin for Esophageal Candidiasis • CID 2004:39 (15 September) • 771
Selected demographic and baseline characteristics
treatment arms. For testing the hypothesis, the 2-sided 95% CI of study participants.
for the difference in endoscopic success rates (rate for the an-idulafungin minus rate for the fluconazole arm) at the end of therapy was calculated. Noninferiority was concluded if the lower bound of the 95% CI was greater than Ϫ10%. Time to resolution of symptoms was summarized using Kaplan-Meier estimates. Duration of therapy was compared between the 2 treatment arms using Student’s t test.
Patients.
The trial was conducted during the period of April 2001 through October 2002. Patients were enrolled from sites in the Republic of South Africa (453 patients), Thailand (91 patients), Argentina (51 patients), and the United States (6 patients). Of 601 randomized patients, 300 received anidula- fungin and 301 received fluconazole. Demographic and baseline characteristics were comparable between treatment groups, with no statistically significant differences (table 1). Most pa- tients had AIDS, although few patients were receiving antiret- roviral drugs at baseline (7 patients in the fluconazole arm and 3 patients in the anidulafungin arm). However, more patients in the fluconazole arm than in the anidulafungin arm started Data are no. (%) of patients, unless otherwise indicated.
receiving antiretroviral therapy during the course of antifungal a Ethnic information for 1 patient in the anidulafungin group is missing.
treatment (58 vs. 26 patients). All patients received a diagnosisof esophageal candidiasis. The groups were well matched with sponse (a successful response was defined as proven or pre- regard to prior antifungal use (mostly nystatin); however, prior sumed eradication of Candida species present at baseline). All use of fluconazole was rare: only 9 patients (4 in the anidu- responses, including endoscopic response, were evaluated for lafungin arm and 5 in the fluconazole arm) reported such prior the intent-to-treat and evaluable populations at the end of ther- use. The disease characteristics of esophageal candidiasis as- apy and at the follow-up visit. In addition, the time to reso- sessed at baseline were similar between the treatment groups.
lution of symptoms and the duration of therapy were Overall, 97.7% of patients in the anidulafungin group and 97.0% of patients in the fluconazole group experienced odyn- The evaluable population consisted of patients who com- ophagia/dysphagia, and 79.7% and 76.7% of the anidulafungin- pleted у10 days of therapy, had an end-of-therapy assessment and fluconazole-treated patients experienced retrosternal pain, with a clinical outcome other than indeterminate, had an en- respectively. The highest proportion of patients had severe doscopic result recorded at the end of therapy, and did not (grade 3) endoscopy grades (table 1).
have any protocol violations up to the end of therapy visit that Mycological diagnosis was confirmed by microscopy for impacted the assessment of efficacy. All safety analyses wereperformed with the intent-to-treat population, which consisted Endoscopic responses at the completion of intrave-
of all randomized patients who received у1 dose of study drug.
nous anidulafungin or oral fluconazole therapy.
Safety.
Safety assessments (hematological analysis, chem- istry, urinalysis, determination of vital signs, physical exami- nation, and 12-lead electrocardiography) were performed throughout the study. Adverse events were assessed daily, at the end of therapy, and at the follow-up visit. Treatment-related adverse events were those considered by the investigator to bepossibly or probably related to use of study medication or those with an unknown relationship to use of study medication.
Statistical analysis.
ses, Pearson’s x2 test was used to compare the proportion of patients with success in the anidulafungin and fluconazole 772 • CID 2004:39 (15 September) • Krause et al.
Clinical and mycological success at the completion
occurred in у2% of patients treated with anidulafungin. The of intravenous anidulafungin or oral fluconazole therapy.
most common drug-related adverse events are shown in table5. One patient in the anidulafungin group experienced a sub- jective sensation of “flushing” associated with the infusion. Nopatient experienced hypotension, wheezing, or anaphylaxis.
The number of serious adverse events related to or possibly related to use of a study drug was low in both treatment arms (2 serious events in each). In the anidulafungin arm, the events were a maculopapular rash in one patient and multisystemorgan failure in the other. The latter patient had multiple com-orbid conditions, including cor pulmonale with right-side con- 98.7% of patients in the anidulafungin group and for 97.7% gestive heart failure, bronchiectasis, and recently treated tu- of patients in the fluconazole group. Of the 442 patients with berculosis. The patient died on study day 3 of a presumed culture-confirmed esophageal candidiasis, 401 had C. albicans cardiorespiratory arrest attributed to his underlying illness. The as the sole baseline pathogen, 7 had Candida glabrata, 1 had serious drug-related adverse events in the fluconazole arm were C andida tropicalis, and 9 had an unspeciated Candida isolate.
pancytopenia and renal failure. Study medication was discon- The remainder had coinfection with 2 Candida isolates.
tinued for 5 patients because of a drug-related adverse event Efficacy analyses.
(the 4 aforementioned patients plus 1 fluconazole recipient with with the protocol and were evaluable for efficacy analyses at rash). During the course of the study, there were 43 deaths (23 the end of therapy. Of these, 242 (97.2%) of 249 patients in in the anidulafungin group and 20 in the fluconazole group).
the anidulafungin group had endoscopic success (i.e., cure or Patients in both study arms manifested minor effects on improvement), compared with 252 (98.8%) of 255 patients in hematological and hepatic parameters with a similar frequency.
the fluconazole group (table 2). The treatment difference of The most common treatment-related laboratory adverse events Ϫ1.6% had an associated 95% CI of Ϫ4.1 to 0.8, thus meeting were increased g-glutamyl transferase level (4 patients in each the predefined criteria for noninferiority. In both groups, most group), elevated aspartate aminotransferase (AST) level (1 pa- endoscopic successes were cures (i.e., an endoscopic grade of tient in the anidulafungin group and 7 patients in the flucon- 0; 88.0% in the anidulafungin and 93.3% in the fluconazole azole group), and increased alanine aminotransferase level (3 group). An intent-to-treat analysis of endoscopic response at patients in the fluconazole group). There were no important the end of therapy showed similar success rates for anidula- discernible differences between groups with regard to changes fungin (86.7%) and fluconazole (88.0%) (95% CI, Ϫ6.7 to 3.9).
in the AST, alanine aminotransferase, alkaline phosphatase, bil- For both treatment arms, the clinical (i.e., symptomatic) suc- irubin, or g-glutamyl transferase level over the course of cess rate was high (table 3). Almost all clinical successes were cures (97.2% and 98.0% for the anidulafungin and fluconazolearms, respectively). Time to resolution of symptoms was also DISCUSSION
similar, as was the mean duration of therapy (table 4). Results To our knowledge, this study represents the largest controlled of the intent-to-treat analysis were similar to the findings of efficacy trial involving patients with esophageal candidiasis, the analysis of evaluable patients. Mycological success was having enrolled 601 patients with documented disease. The achieved in the majority of evaluable patients at the end oftherapy in both arms (table 3).
Time to resolution of symptoms and duration of intra-
At the 2-week follow-up visit, 462 patients underwent en- venous anidulafungin or oral fluconazole therapy.
doscopy and were otherwise evaluable for a follow-up evalu-ation. Of these, 150 (64.4%) of 233 patients who received an- idulafungin and 205 (89.5%) of 229 patients who received fluconazole had sustained endoscopic success (95% CI, Ϫ32.5% Safety evaluation.
fungin-treated patients and 226 (75.1%) of 301 fluconazole- treated patients reported у1 adverse event. Treatment-related (per investigator attribution) adverse events were reported by 28 (9.3%) and 36 (12.0%) patients in the anidulafungin and fluconazole groups, respectively. No drug-related adverse events Odynophagia/dysphagia and retrosternal pain.
Anidulafungin for Esophageal Candidiasis • CID 2004:39 (15 September) • 773
Patients with treatment-related adverse events, by
eters were infrequent in both study arms, although more pa- body system.
tients in the fluconazole group had treatment-related (per in-vestigator attribution) increases in the AST level. In addition, the frequency of infusion-associated systemic reactions ap- peared to be very low or nonexistent in this study.
The rate of successful outcomes in this study is as high, or higher, than historical rates with systemic antifungals for treat- ment of esophageal candidiasis [5, 29, 30]. The distribution of baseline isolates was consistent with the epidemiology of esoph- ageal candidiasis [4, 6] in the United States and elsewhere and thus should be generalizable. The data from this study indicate that anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis, when assessed at the completion of therapy. Anidulafungin is well tolerated and may be a valuable treatment alternative for patients with esoph- ageal candidiasis, particularly for those who are intolerant oforal therapy or other parenteral agents. Clinical trials with an- Adverse events occurred in у1.0% of patients; relationship to use of study drug was determined by the investigator to be possibly or probably idulafungin in patients with fluconazole-refractory orophar- yngeal and esophageal candidiasis and with invasive candidiasisare currently in progress.
treatment groups were well matched with respect to demo-graphic variables and disease severity. The majority of patientsin each group had AIDS. As is typical of esophageal candidiasis, Acknowledgments
195% of patients with available culture results had C. albicans We would like to acknowledge the contribution of Prudence Ive, Lucy identified at baseline. Compliance with the protocol was ex- Connell, Glenda Gray, J. H. Mynhardt, Mariette Botes, Trevor Winter, Louis cellent: 84% of patients remained in the evaluable population van Zyl, Johannes Roos, and D. M. Kelbe (South Africa); Somit Tansu- phaswadikul, Comson Lertkupinet, and Piroon Mootsikapun (Thailand);Alvaro Reymunde (Puerto Rico); Jose Vazquez (United States); and Jorge Because of the high recurrence rate associated with esoph- Olmos, Pedro Cahn, Jorge Corral, Ricardo Negroni, Javier Altclas, Hector ageal candidiasis [8], the end of therapy was prospectively de- Laptume, Lucila Massera, Sergio Lupo, Daniel David, and Ricardo Lam- fined as the primary time point of interest. In this immuno- berghini (Argentina), for enrolling patients. We also thank Taylor Kilfoil compromised population, anidulafungin was as efficacious as (Inclin; San Carlos, CA) for project management, Deborah Matour (DLMatour & Co.; Harleysville, PA) for preparation of the manuscript, Michael fluconazole, the current standard of care. Both drugs dem- Pfaller (University of Iowa; Iowa City) for the mycology central laboratory, onstrated high rates of endoscopic response, clinical cure, and and John Rex (University of Texas, Houston; currently at AstraZeneca, mycological response in both the evaluable population and the Macclesfield, UK) for assistance with trial design.
Financial support.
Conflict of interest.
D.S.K., T.H, M.W., and B.P.G. are employees of The results of this study underscore the high recurrence rate Vicuron Pharamaceuticals, the manufacturer of anidulafungin. T.J.W. has for this illness [8]. A lower sustained response rate was noted received research funding from Vicuron Pharmaceuticals and has a Co-operative Research and Development agreement with Fujisawa. All other in the anidulafungin-treated patients at the 2-week follow-up.
More patients in the fluconazole arm than in the anidulafunginarm received antiretrovirals during study treatment, potentiallyconfounding the findings at follow-up. An earlier randomized References
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