Comparison of Oral Fluconazole and Itraconazole for Progressive, Nonmeningeal Coccidioidomycosis

Coccidioidomycosis is a systemic fungal infection caused by Coccidioides immitis. Typically, infection stimulates a protective immune response that limits the initial illness and confers lifelong resistance to subsequent infections (1). Occasionally, however, illness progresses, either as a fibrocavitary chronic pneumonia or hematogenously, with dissemination of infection to such extrathoracic sites as the skin, bones, or joints (2, 3). If these complications occur, antifungal therapy is warranted to prevent further tissue destruction and associated morbidity (4). Azole antifungal agents have become valuable in treating progressive forms of coccidioidomycosis, especially when disease manifestations are not fulminant or immediately life-threatening. Originally, the U.S. Food and Drug Administration approved intravenous miconazole and oral ketoconazole for this indication on the basis of their efficacy and safety (5-14). The lack of an oral form of miconazole and untoward effects or drug intolerance related to both agents led to the development of fluconazole, itraconazole, and related congeners. These new drugs have shown therapeutic efficacy against coccidioidomycosis in experimental infections of animals (15-20) and in subsequent clinical trials (21-30). Our current understanding of optimal management of coccidioidal infections is severely limited by the absence of randomized comparative trials that evaluate the different forms of therapy. Multicenter comparative trials are now possible because over the past decade, the evaluation of patients treated for coccidioidomycosis has become standardized. In addition, because of the development of a collaborative group during the same period, trials can now enroll enough patients to support clinically applicable results. In this report, we present the findings from Mycoses Study Group Protocol 20, a comparative trial sponsored by the National Institute of Allergy and Infectious Diseases that compares two antifungal agents, fluconazole and itraconazole, in the treatment of coccidioidomycosis. Methods Patient Eligibility Patients were considered for enrollment if C. immitis was identified by culture, by microscopic examination of infected tissue from outside the lungs, or from respiratory specimens, if a pulmonary infection had persisted for more than 3 months. Patients with HIV infection and pulmonary coccidioidomycosis of shorter duration were eligible if their CD4 count was less than or equal to 0.25 109 cells/L or if they had diffuse bilateral pneumonia. Enrollees had to be able to take oral medications. Pregnant women were excluded, and women of childbearing potential were required to practice an effective method of birth control. Patients who had received more than 4 mg/kg of body weight of amphotericin B or more than 8 g of an azole antifungal agent for the current episode of infection were ineligible. Other exclusion criteria were immediately life-threatening coccidioidomycosis, presence of coccidioidal meningitis, concomitant administration of a nonstudy systemic antifungal drug, history of hypersensitivity to an azole compound, insufficient evidence of infection on which to assess a response to treatment, renal insufficiency (defined as a serum creatinine concentration>180 mol/L [2.0 mg/dL]), or any of the following abnormal laboratory test values at baseline: hemoglobin level less than 4.3 mmol/L (7 mg/dL), absolute neutrophil count less than 0.8 109 cells/L, platelet count less than 0.5 109 cells/L, liver enzyme levels (alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase) more than 7.5 times the upper limit of normal, or bilirubin level more than 2 times the upper limit of normal. In addition, we excluded patients receiving concomitant medications that could not be managed safely in a blinded study because of potential interactions with the study drugs. The institutional review boards of each participating center approved the study protocol, and signed consent was obtained from each patient before enrollment. Randomization and Management of Therapy This was a double-blind study in which the patient and the investigators were unaware of the identity of the study medications. For patient enrollment, a primary investigator contacted a central study coordinator, who reviewed the completeness of the patient's eligibility and categorized the major site of infection as chronic pulmonary, soft tissue, or skeletal. Patients in each of the three major categories were randomly assigned to receive fluconazole and itraconazole in a 1:1 ratio. Pharmacists at each participating institution dispensed appropriate medication according to the randomization code that they had been given. The randomization code was stored securely by the pharmacists at each study site, and pharmacists never informed patients, investigators, or other clinical personnel of the patient's designated treatment. Any requests by the primary investigators for unblinding treatment were handled by the principal investigator of the Mycoses Study Group, who was not a collaborating investigator of this study. The fluconazole tablets (supplied by Pfizer, New York, New York) and itraconazole tablets (supplied by Janssen Pharmaceutica, Piscataway, New Jersey) differed in appearance. Therefore, to maintain blinded treatment, a double placebo design was used. Patients randomly assigned to fluconazole received 400 mg of active fluconazole once daily and placebo itraconazole twice daily. Conversely, patients randomly assigned to itraconazole received 200 mg of active itraconazole twice daily and placebo fluconazole once daily. Therefore, each patient simultaneously received a combination of an experimental study drug and a placebo. Medications were administered orally with meals. Treatment lasted 8 months before the primary outcome assessment and continued for another 4 months to consolidate a response. Patient Assessment At enrollment, all patients provided a complete history, underwent a physical examination, submitted blood specimens for baseline hematologic and chemistry analyses, and were further evaluated with appropriate imaging procedures to determine the extent of evident infection. A central laboratory determined complement-fixing type anticoccidioidal antibodies in serum specimens by using the quantitative immunodiffusion technique (31). Enrolled patients were interviewed and examined at 2 weeks, 4 weeks, 2 months, and every 2 months thereafter while receiving study medication to assess protocol adherence, to determine possible adverse drug effects, and to ensure that the disease was not progressing. Disease activity was assessed at 4, 8, and 12 months. For some patients, especially those with skeletal lesions, computed tomography and magnetic resonance imaging studies were used to assess disease activity. To assess the extent of infection, we used a previously described scoring strategy (22). In brief, symptoms, appearance of lesions, serum anticoccidioidal antibody titers, and culture results that were repeated during the study were assigned numerical values according to a predefined set of rules. The sum of these values at reassessment during therapy was compared with that determined at enrollment. An increasing score reflected a poorer condition and a decreasing score reflected an improved condition. Response to therapy was defined as a 50% reduction in baseline abnormalities during the first 8 months of therapy. Relapses were considered to have occurred in responding patients who discontinued all antifungal therapy if therapy was reinstituted because an existing coccidioidal lesion worsened or a new coccidioidal lesion developed. Determination of Serum Drug Concentrations Serum specimens were collected from patients 1 month, 4 months, and 8 months after the start of therapy. Specimens were mailed to a central laboratory and stored at 70 C until protocol therapy was concluded on all patients; all specimens were then assayed at one time. Fluconazole levels were measured by using gasliquid chromatography (32), and itraconazole levels (itraconazole and hydroxyitraconazole) were measured by using bioassay (33). The lower limit of detection was 0.2 g/mL for fluconazole and 0.5 g/mL for itraconazole. Statistical Analysis The primary null hypothesis, which we hoped to reject, was that the efficacy of fluconazole and itraconazole after 8 months of treatment was equal in favor of the alternative hypothesis (at least 20% superiority of one treatment). Past studies on nonmeningeal progressive coccidioidomycosis indicated that between 55% and 65% of patients should respond to 400 mg of either azole drug per day (22, 29). With a response rate of 55%, a two-sided type I error of 5%, and a power of 0.8, 196 patients would be required to show a 20% difference in the efficacy of the two treatments. We planned to enroll 4 additional patients to accommodate any ineligible cases; therefore, accrual was to be 200 patients. Enrollment was closed with 198 patients after reaching a termination date that had been agreed to in advance by the pharmaceutical sponsors, the Mycoses Study Group, and the National Institutes of Health. The primary outcome analysis was performed on an intention-to-treat basis at 8 months on all patients, regardless of whether they reached an end point or discontinued the protocol prematurely. For treatment to be considered successful, a patient had to be evaluated at 8 months and have a score less than or equal to 50% of the baseline score. Patients who did not meet these criteria were considered to be nonresponding. Consolidation therapy continued for 4 months to complete 1 year of protocol treatment. Two interim analyses were performed during the trial. The levels of significance maintained an overall P value of 0.05 and were calculated according to the O'BrienFleming stopping boundaries. This final analysis used a Z score of 1.985 with an associated P value of 0.0471 (3