itraconazole-ampho capsules comparison

8/8/2019 Itraconazole-Ampho Capsules Comparison

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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,0066-4804/00/$04.000

July 2000, p. 18871893 Vol. 44, No. 7

Copyright 2000, American Society for Microbiology. All Rights Reserved.

Itraconazole Oral Solution for Primary Prophylaxis of FungalInfections in Patients with Hematological Malignancy and

Profound Neutropenia: a Randomized, Double-Blind,Double-Placebo, Multicenter Trial ComparingItraconazole and Amphotericin B

J. L. HAROUSSEAU,1 A. W. DEKKER,2 A. STAMATOULLAS-BASTARD,3 A. FASSAS,4 W. LINKESCH,5

J. GOUVEIA,6 R. DE BOCK,7 M. ROVIRA,8 W. F. SEIFERT,9 H. JOOSEN,9

M. PEETERS,9 AND K. DE BEULE9*

Hopital Dieu, Nantes,1 and Centre Henri Becquerel, Rouen,3 France; University Hospital, Utrecht, The Netherlands2;George Papanikolaou General Hospital, Thessalonika, Greece4 ; Medizinische Universitatsklinik, Graz, Austria5;

Hospital Dos Capuchos, Lisbon, Portugal6 ; Algemeen Ziekenhuis Middelheim, Antwerp,7 and JanssenResearch Foundation, Beerse,9 Belgium; and Hospital Clnic IDIBAPS, Barcelona, Spain8

Received 2 December 1999/Returned for modification 9 February 2000/Accepted 24 April 2000

Systemic and superficial fungal infections are a major problem among immunocompromised patients withhematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed tocompare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) withamphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungalinfection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until theend of the neutropenic period (>0.5 109 neutrophils/liter) or up to a maximum of 3 days following the endof neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatmentduration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericinB; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergil-losis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oralamphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as comparedto oral amphotericin B (2 [1%] versus 13 [5%]; P 0.004). Although the incidences of suspected fungalinfection (including fever of unknown origin) were not different between the groups, fewer patients were

administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receivingitraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P 0.066).

Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start oftreatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration ofitraconazole oral solution significantly reduces superficial fungal infection in patients with hematologicalmalignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths dueto deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treatedgroup than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution isa broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially forthose at high risk of prolonged neutropenia.

Among neutropenic patients with hematological malig-nancy, infections remain a major problem. Nowadays, themajority of bacterial infections can be treated or prevented

successfully by using broad-spectrum antibiotics. Fungal infec-tions, on the other hand, remain a common cause of morbidityand mortality in patients at risk of neutropenia (1). Moreover,during the past two decades, the incidence of fungal infectionsin this patient population has increased dramatically, the majorpathogens being Candida spp. and Aspergillus spp.

Systemic fungal infections remain the major cause of deathin neutropenic patients with hematological malignancy, andoptimal management of these opportunistic infections is a ma-jor challenge for clinicians. Among the measures that can be

taken to prevent fungal infections, environmental and hygieniccontrol and elimination of well-known sources of infection areimportant.

Early studies of the prophylactic use of oral drugs like am-photericin B, nystatin, clotrimazole, miconazole, and ketocon-azole yielded unsatisfactory results because of poor absorption,a narrow spectrum, poor compliance, and toxicity (4; E. J. Bow,M. Laverdiere, N. Lussier, C. Rotstein, and S. Ioannou, Abstr.37th Intersci. Conf. Antimicrob. Agents Chemother., abstr.LM-88, p. 381, 1997). Neutropenic patients with persistentfever refractory to antibiotic treatment are often treated em-pirically with intravenous amphotericin B, despite its toxicity.Prophylactic treatment with fluconazole, an azole antifungalagent (15), is widely used nowadays. However, fluconazole,either oral or intravenous, offers no protection against Aspergil-lus spp., and several pathogenic Candida spp. are either resis-tant (C. krusei) or less sensitive (C. glabrata) to this compound(8, 17, 18). Intranasal administration of amphotericin B did not

* Corresponding author. Mailing address: Janssen Research Foun-dation, 2340 Beerse, Belgium. Phone: 32 14 60 34 43. Fax: 32 14 60 2976. E-mail: [email protected].

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show a significant benefit over placebo as prophylaxis againstaspergillosis, and although the liposomal formulations of am-photericin B seem to be safer, the clinical efficacy has not yetbeen proven, and few data are available with regard to pro-phylaxis (14). Moreover, prophylactic treatment with these li-posomal formulations is expensive, thereby limiting its poten-tial as a commonly used prophylactic agent (6). Itraconazole is

a broad-spectrum triazole antifungal agent currently availableas a capsule formulation for the treatment of systemic mycosessuch as aspergillosis, candidosis, cryptococcosis, histoplasmo-sis, and several endemic mycoses; it has demonstrated clinicalactivity against Aspergillus infections (3). The newer oral solu-tion formulation (10% itraconazole in a 40% hydroxypropyl--cyclodextrin [HDCD] solution) has overcome the limita-tions of the capsule formulation in that both adequate plasmadrug concentrations are reached in the neutropenic host (12,13) and it can be administered with or without food (2, 16).The prophylactic use of itraconazole oral solution offers analternative at least as effective as fluconazole (10). Treatmentwith this cyclodextrin-containing solution is well tolerated (11).

This trial was initiated to compare the efficacy of itracon-azole oral solution with nonabsorbable oral amphotericin B inthe prevention of systemic and superficial fungal infections inpatients with hematological malignancy and profound neutro-penia. Furthermore, the frequency of and the time to initiationof intravenous systemic antifungals (e.g., amphotericin B) werecompared.

MATERIALS AND METHODS

Patients. Male or female patients of at least 18 years of age, with a lifeexpectancy of at least 14 days, and who had one of the following underlyingconditions were eligible for this trial: acute leukemia scheduled for remission orinduction or consolidation or reinduction chemotherapy; autologous bonemarrow transplantation; myelodysplastic syndrome and scheduled to receiveleukemia-like cytostatic therapy; chemotherapy for the blast crisis of chronicmyelogenous leukemia; or lymphoma or myeloma and undergoing aggressivechemotherapy (e.g., platinum-based salvage regimen). In addition, their neutro-

phil count was expected to be 500/l for at least 14 days, and they were not tohave signs or symptoms of fungal infection (fungal colonization was allowed).Informed consent was obtained from each patient or from the patients relative,guardian, or representative. Patients were excluded from the trial if they hadbeen diagnosed with a proven or suspected deep fungal infection (including allcases without mycological sampling) during previous episodes of neutropenia,presented with a chest X ray suggestive of fungal infection, or with a fever ofunknown origin (38.5C, rectal temperature), had received systemic antifungaltherapy within 2 weeks before trial entry or topical intraoral antifungal therapywithin 1 week before trial entry, were receiving terfenadine, astemizole, phenyt-oin, phenobarbital, rifampin, warfarin, loratadine, oral midazolam, triazolam, orcisapride or had received these medications in the 2-week period prior to trialentry or were expected to receive granulocyte-macrophage-colony-stimulatingfactor (GM-CSF), M-CSF, interleukin 3 (IL-3) or other growth factors (exceptfor G-CSF, which was allowed). Women who were known to be pregnant orbreast feeding, or who were of childbearing potential and not practicing ade-quate birth control were also excluded, as were patients who were unable to takeoral medication, had liver disease defined as liver enzyme levels (alanine ami-

notransferase [ALAT] or aspartate aminotransferase [ASAT])

4 times theupper normal limit at trial entry, were receiving investigational drugs other thananticancer regimens concurrently or within 1 month prior to trial entry, hadpreviously shown hypersensitivity to azole antifungals or to oral amphotericin B,were known to be human immunodeficiency virus positive, had profuse diarrheaon presentation, or were entered into the trial previously.

Independent Ethics Committees approved the trial protocol and the amend-ments.

Treatments. Patients were, on the basis of a computer-generated randomiza-tion list, grouped in blocks of four, assigned to receive double-blind, double-placebo treatment with one of the two active trial substances. Because of thedouble-blind, double-placebo nature of the trial, patients received both thesolution and the capsule regimen: they received either active itraconazole solu-tion together with placebo capsules or active amphotericin B capsules togetherwith placebo solution. Prophylaxis was started on the first day of chemotherapy.Itraconazole oral solution (2.5 mg/kg of body weight twice a day) was providedas 100-ml bottles containing 100 mg of itraconazole per 10 ml of HPCDsolution or HPCD-identical placebo. Oral amphotericin B (500 mg four timesa day) was administered as 250-mg (Fungizone) capsules or identical placebo

capsules. The trial medications were preferably to be taken without a meal. Theoral solution was to remain in contact with the oral mucosa for at least 10 s andthen was swallowed; it was not to be diluted.

Treatment was continued up to the end of neutropenia or up to a maximum of3 days following the end of neutropenia, unless a trial end point had beenreached earlier. The maximum treatment duration was 8 weeks (56 days).

Effectiveness assessments. The leukocyte count and the neutrophil count wererecorded at baseline and during prophylaxis, daily, or at least three times weekly.All changes in urinary and intravenous catheters were to be recorded. Removed

catheters were examined for the presence of yeast or molds in case of a fungaltrial end point. Identification of the isolated yeast or mold was always to be doneup to the species level. A chest X ray was to be carried out at baseline and weeklythereafter during prophylaxis. Signs and symptoms potentially attributable tosuperficial or deep fungal infection were recorded. Both during and after pro-phylaxis, additional tests (biopsy, computed tomography [CT] scan, chest X ray,and bronchoalveolar lavage [BAL]) were to be carried out whenever possible andacceptable in terms of the clinical condition of the patient. In addition, BAL wasto be carried out in case of pulmonary infiltrates. In the case of the CT scan,high-resolution scanning was to be utilized.

Trial end point. Prophylactic treatment was stopped at the end of the neutro-penic period, when a fungal infection trial end point was reached earlier, or whenthe investigator considered it, for safety reasons, in the best interest of thepatient that or he/she be withdrawn. The end of neutropenia was defined as atleast one neutrophil count higher than 500/l. The fungal infection trial endpoint was classified according to one of the following criteria.

(i) Proven deep fungal infections were defined as positive histology on biopsyfrom deep tissue, at least one positive blood culture for yeasts, or clinical signs

and radiological lesions in combination with the presence of Aspergillus spp. orother filamentous fungi in BAL fluid.

(ii) Suspected deep fungal infections were defined as clinical signs and symp-toms (with or without radiological lesions) with fever of unknown origin unre-sponsive to broad-spectrum antibacterials, highly suggestive radiological lesions(X ray and CT scan) for deep fungal infection without mycological evidence byculture or histology (e.g., hepatosplenic candidosis and some types of pulmonaryaspergillosis), or clinical signs and symptoms (with or without radiological le-sions) not highly suggestive of fungal infection, but associated with suggestivefungal isolation (e.g., from sputum or nasal cavities for aspergillosis).

(iii) Fever of unknown origin requiring empiric treatment with intravenousamphotericin B was defined as fever of unknown origin for at least 48 h onbroad-spectrum antibiotics without clinical signs and symptoms.

(iv) Superficial fungal infections were defined as clinical signs and symptoms oforal, esophageal, or vaginal candidosis combined with positive mycology at thesite of infection; documented oral or vaginal candidosis only resulted in stoppingthe trial prophylaxis in case systemic antifungal treatment was required.

The prophylaxis end point was recorded when the trial medication was dis-

continued. The postprophylaxis end point was recorded within 4 weeks after theprophylaxis end point. At this administrative visit, all available evidence forfurther characterization of a fungal infection was collected. If the postprophy-laxis end point was not recorded, the prophylaxis end point and the postprophy-laxis end point were considered to be identical.

Assessments by the independent Expert Committee. The Expert Committeeclassification was a reclassification of the investigators postprophylaxis endpoint. The Expert Committee, which was composed of three members withspecific expertise on fungal infections during neutropenia and not participatinginto the trial, was provided with copies of all test results used to substantiate adiagnosis, the original CT scan or X rays providing evidence of fungal infection,as well as data on autopsy or immediate postmortem biopsies in order to enablethem to reevaluate the classification of all trial end points prior to analysis. Thisfinal overall assessment was carried out blinded for the prophylactic trial med-ication.

Plasma drug concentrations A 5-ml blood sample was taken immediatelybefore the morning intake once weekly during prophylaxis and at the end ofprophylaxis for the measurement of plasma itraconazole and hydroxyitracon-azole concentrations. Date and hour of sampling and of the intake of studymedication in the 24-h period before sampling were recorded. Concentrations ofitraconazole and hydroxyitraconazole in plasma were determined by high-per-formance liquid chromatography with UV detection. The quantification limit ofthe assay was 10 ng/ml.

Safety assessments. The date of onset and duration of any adverse event thathad occurred during the trial period (including any intercurrent disease) werenoted, as well as their intensity, frequency, action taken, presumed drug relat-edness, and outcome. The occurrence of serious adverse events was documented.Laboratory parameters (potassium, sodium, calcium, ALAT, ASAT, alkalinephosphatase, -glutamyltransferase, total cholesterol, creatinine, urea, and totalbilirubin) were determined at selection and on a twice-weekly basis during thetrial.

Statistical analysis. The statistical analysis of all data was performed by theJanssen Research Foundation. The primary population was the intent-to-treatpopulation, which included all randomized patients with at least one drug ad-ministration. The subgroup of patients with neutropenia of0.5 109/liter forat least 14 days (i.e., high-risk patients for fungal infection) was also analyzed.

1888 HAROUSSEAU ET AL. ANTIMICROB. AGENTS CHEMOTHER.


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The comparability among the trial groups was evaluated relative to demographicand baseline variables.

The incidence of invasive aspergillosis according to the classification of theExpert Committee was the primary efficacy parameter. A reduction from 5% in

the amphotericin B arm to 1% in the itraconazole arm was postulated. There-fore, data from 250 neutropenic patients were required in each group to achievethe 5% significance level (two sided) with 80% power. Based on a 20% dropoutrate, 640 subjects were to be randomized. An interim analysis was planned forthe 400 patients first randomized. Based on the results of this blinded interimanalysis, it became evident that the required number of documented cases ofaspergillosis could not be obtained by recruiting all 640 patients as stipulated inthe sample size calculation. Therefore, the trial was stopped at the time of theinterim analysis, when 559 patients were randomized to treatment.

Dichotomous parameters were analyzed with the Pearson chi-square test,time-to-an-event parameters were graphically presented using the Kaplan-Meierestimate and compared between the treatment groups by using the log-rank testfor censored data, and continuous and ordinal categorical data were comparedby means of the Mann-Whitney U test. Additionally, a Cox proportional hazardsmodel with factors for treatment and country was applied for time to first use ofamphotericin B. To investigate possible country effects, the Cochran-Mantel-Haenszel test controlling for country was applied.

Descriptive statistics (mean standard deviation, mean, minimum to maxi-mum) were calculated for the minimum concentration of drug in serum ofitraconazole and hydroxyitraconazole for the plasma samples at specified inter-vals after the start of treatment.

The type and incidence of adverse events were tabulated per treatment group.Special attention was paid to drug-related adverse events, serious adverse events,and other significant adverse events (i.e., those leading to the patients withdraw-al). For the clinical laboratory data, descriptive statistics and pre- versus within-and posttreatment cross-tabulations (with classes for below, within, and abovethe normal range of the particular laboratory) were generated for all testsperformed. In addition, important abnormalities were tabulated.

RESULTS

Investigators from 49 centers in seven different countries(Austria, Belgium, France, Greece, The Netherlands, Portugal,and Spain) recruited 557 patients (from July 1994 to April1997) who were randomized to treatment: 281 received itra-

conazole, and 276 were given amphotericin B (intent-to-treatpopulation).

There were no significant intergroup differences in baseline

characteristics; data on sex, age, underlying disease, therapy ofthe underlying disease, duration of neutropenia, and durationof treatment are summarized in Table 1. The median (mini-mum to maximum) durations of neutropenia were 18 (0 to 84)days in itraconazole-treated patients and 20 (0 to 88) days inamphotericin B-treated patients. In line with these results, themedian durations of treatment were 19 (1 to 56) days in theitraconazole group and 18 (2 to 56) days in the amphotericin Bgroup. The main underlying pathology was leukemia (71% ofthe patients in each group).

Invasive aspergillosis. Invasive aspergillosis was docu-mented in five (1.8%) itraconazole-treated patients and in nine(3.3%) amphotericin B-treated patients (P 0.264) (Table 2);of these, only one patient in the itraconazole group compared

with four patients in the amphotericin B group died (Table 3).The pathogens that were identified were Aspergillus fumigatusin all cases, except for one in the amphotericin B group (As- pergillus terreus) (Table 3).

In the amphotericin B group, all nine patients were positivefor Aspergillus spp. in BAL fluid, whereas this was the case inonly two out of five patients in the itraconazole group. Of thethree remaining itraconazole-treated patients, one had positiveAspergillus cultures from the nose and sputum and was diag-nosed by the Expert Committee as having invasive pulmonaryaspergillosis (biopsy and CT scans), one patient had positivecultures obtained from nose and stools (X ray, CT scan, andbiopsy), and the remaining patient was graded by the ExpertCommittee as having a proven aspergillosis infection based ona very typical halo sign on serial X rays and the CT scan. In the

TABLE 1. Patient and disease characteristics at the start of treatment, duration of neutropenia, and duration of prophylactic treatment

Intent-to-treat population parameterResult with:

Itraconazole Amphotericin B

Patient and disease characteristics at the start of treatmentNo. of patients randomized (male/female) 281 (167/114) 276 (147/129)

Age; median (minimummaximum) yr 48 (1575) 49.5 (1782)

Underlying disease; n (%) Acute myeloid leukemia 166 (59) 153 (55) Acute lymphatic leukemia 33 (12) 42 (15)Other 83 (29) 81 (29)

Therapy of underlying disease; n (%)Chemotherapy 232 (89) 221 (88)Bone marrow transplant 14 (5) 13 (5)Other 14 (5) 16 (6)Not recorded 21 26

Status of disease; n (%)First treatment 188 (79) 184 (76)Other 51 (21) 58 (24)

Not recorded 42 34

Duration of neutropenia and duration of prophylactic treatmentDuration of neutropenia of0.5 109 /liter; median (minimummaximum) days 18 (084) 20 (088)

Use of G-CSF 83 81

Duration of prophylactic treatment; median (minimummaximum) days 19 (156) 18 (256)

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majority of the cases, classification of aspergillosis was furthersupported by CT scan, X rays, or both.

Other fungal infections. Apart from invasive aspergillosis,other proven deep fungal infections were noted in three(1.1%) patients in the itraconazole group and in four (1.4%)

patients in the amphotericin B group (Table 2; P is not signif-icant); of these, none of the itraconazole patients and oneamphotericin B patient died (Table 3). In the amphotericin Bgroup, all four fungal infections were documented in the blood.(Candida krusei, Candida parapsilosis, Geotrichium spp., and Fusarium nygamai were each noted in one patient.) In theitraconazole group, one patient had a Candida albicans infec-tion of the blood, one had a skin biopsy positive for Crypto-coccus neoformans (maculopapular eruptions), and one had apositive culture for Candida glabrata (pus and an abscess in theright iliac fossa).

The incidence of superficial fungal infections was signifi-cantly higher in the amphotericin B group than in the itracon-azole group: 13 (5%) versus 2 (1%; P 0.004). Also, the totalnumber of patients with a proven fungal infection (i.e., proven

deep fungal infection including invasive aspergillosis and su-perficial fungal infection) was significantly higher in the am-photericin B group (26 [9.4%]) than in the itraconazole group(10 [3.6%]) (P 0.005). Suspected deep fungal infections(including fever of unknown origin) were noted in a compara-ble number of patients in the two groups: i.e., 83 (30%) in theitraconazole group and 80 (29%) in the amphotericin B group.

Initiation of systemic antifungal treatment. During the trial,systemic antifungal treatments (intravenous amphotericin B[any formulation], fluconazole, and voriconazole) were initi-ated in 114 (41%) itraconazole-treated patients and in 132(48%) oral amphotericin B-treated patients. The Kaplan-

Meier analysis of time to an event showed that, in the firstquartile of patients, the times to first administration of sys-temic antifungals were 18 days in the itraconazole group and15 days in the amphotericin B group; this intergroup differencetended to be significant (P 0.055). In the analysis of high-riskpatients, these times were 18 and 14 days, respectively; thisintergroup difference was statistically significant (P 0.029)(Fig. 1).

According to the Cox proportional hazard model, the instan-taneous risk of administration of amphotericin B was 33%lower in the itraconazole group than in the amphotericin Bgroup (i.e., risk ratio, 1.326; 95% confidence limits, 0.998 and1.761; P 0.052).

Survival. The overall mortalities were 6% (n 18) in theitraconazole group and 8% (n 23) in the oral amphotericin

B group (P 0.384). Of those, five patients died with a provendeep fungal infection in the oral amphotericin B group versusonly one in the itraconazole group.

Plasma itraconazole concentrations. Mean concentrationsof itraconazole in plasma were 512 ng/ml after 1 week oftreatment and increased further to 764, 1,028, and 1,253 ng/mlafter 2, 3, and 4 weeks of treatment, respectively (Table 4). Theefficacy levels were achieved shortly after initiation of treat-ment. From 1 week after the start of treatment onwards, about80% of the patients had predose concentrations of itracon-azole in plasma greater than 250 ng/ml, which is considered tobe the minimum level required for efficacy. After 4 weeks oftreatment, these levels were attained in 96% of the patients(Table 4).

Two proven fungal infections were diagnosed in the 20%group of patients who did not have a plasma drug level 250ng/ml at the week 1 evaluation. Five proven infections werediagnosed in the 80% group of patients who did reach the250-ng/ml level at week 1. No valid statistical conclusion can bemade with regard to this interrelationship.

Subanalysis of high-risk patients. As outlined in the proto-col, we analyzed the subgroup of all patients with neutropeniaof0.5 109/liter for at least 14 days (201 itraconazole pa-tients and 186 amphotericin B patients). Due to the combina-tion of depth and duration of neutropenia, this group is con-sidered to be a high-risk population for fungal infection.

The analysis confirmed the findings of the main analysis: allcases of invasive aspergillosis (i.e., five [2.5%] in the itracon-azole group and nine [4.8%] in the amphotericin B group)

TABLE 2. Kind and incidence of fungal postprophylaxis end points according to the classification of the Expert Committee

Intent-to-treat populationNo. (% of patients with end point

Pa

Itraconazole (n 281) Amphotericin B (n 276)

Invasive aspergillosis 5 (1.8)b 9 (3.3)c 0.264Proven deep fungal infection (including invasive aspergillosis) 8 (2.8)b 13 (4.7)d 0.248Superficial fungal infection 2 (0.7) 13 (4.7) 0.004

Total proven fungal infection 10 (3.6) 26 (9.4) 0.005Suspected deep fungal infection (including fever of unknown origin) 83 (29.5) 80 (29.0) 0.886

a Intergroup comparison, chi-square test.b One died.c Four died.d Five died.

TABLE 3. Pathogens identified in patients with proven deep fungalinfections after prophylactic treatment with itraconazole or

amphotericin B

Pathogens

No. of patients with pathogen detectedposttreatment

Itraconazole Amphotericin B

Aspergillus fumigatus 5a 8b

Aspergillus terreus 0 1a

Candida albicans 1c 0Candida glabrata 1 0Candida krusei 0 1c

Candida parapsilosis 0 1c

Cryptococcus neoformans 1 0 Fusarium nygamai 0 1c

Geotrichum spp. 0 1a,c

Total 8 13

a One died.b Three died.c Detected in blood.



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were identified in this group (Table 5; P 0.216); also, allother cases of proven deep fungal infections (three in eachgroup), except for one in the amphotericin B group, wereidentified in this group. Overall, the incidence of all provenfungal infections (i.e., proven deep fungal infections, includingaspergillosis and superficial fungal infections) was significantlylower in the itraconazole group (10 patients [5.0%]) than in theamphotericin B group (23 patients [12.4%]; P 0.009). Sig-nificantly fewer itraconazole patients (2 [1%]) than amphoter-icin B patients (11 [6%]) developed superficial fungal infec-tions (P 0.007). The incidences of suspected deep fungal

infections were similar in the two groups (37% for itraconazoleand 39% for amphotericin B versus 29.5 and 29%, respectively,in the total patient sample).

Safety. Adverse events were reported in 222 (79%) itracon-azole-treated patients and in 205 (74%) amphotericin B-treatedpatients. The most frequently reported adverse events were ofgastrointestinal origin (Fig. 2). Rash (17 and 13%, respectively)and hypokalemia (11% for itraconazole and 7% for amphotericinB) were the other most frequently reported adverse events. Theincidences of adverse events were similar in the two groups.

The investigators considered one or more adverse events tobe definitely drug related in 13 (5%) patients in each group.The main drug-related adverse events were local intolerability(five patients in each group), nausea (two itraconazole-treatedpatients and seven amphotericin B-treated patients), and vom-

iting (three and six patients, respectively).

Overall, comparable numbers of patients in both treatmentgroups permanently stopped the treatment because of adverseevents (including death): i.e., 75 (27%) in the itraconazolegroup and 78 (28%) in the oral amphotericin B group; themedian (minimum to maximum) durations of treatment inthese patients were 10 (1 to 45) days in the itraconazole groupand 12 (2 to 28) days in the amphotericin B group. Nausea (9and 11%, respectively) and vomiting (8 and 7%, respectively)were the most frequently reported adverse events leading towithdrawal.

Serious adverse events were reported in 26 (9%) patients in

the itraconazole group and in 32 (12%) of the patients in theamphotericin B group. Of these, 18 (6%) itraconazole-treatedpatients and 23 (8%) amphotericin B-treated patients died.The most frequently reported adverse events with the outcomeof death were aggravated underlying condition (four and fivepatients, respectively), circulatory failure (four and two pa-tients, respectively), sepsis (three subjects in each group), di-arrhea (one patient in the itraconazole group and four in theamphotericin B group), gastrointestinal hemorrhage (four am-photericin B-treated patients), fungal infection (two patients ineach group), and respiratory failure (one patient in the itra-conazole group and three in the amphotericin B group).Changes in biochemical laboratory parameters were compara-ble in the two groups. There were relatively many importantlaboratory abnormalities, but considering this patient popula-

tion, these could be accounted for.

FIG. 1. Time to use of systemic antifungals for eligible patient analysis (neutrophil count of0.5 109 /liter for at least 14 days).

TABLE 4. Plasma itraconazole and hydroxyitraconazole concentrations

Time (n)

ItraconazoleHydroxyitraconazole median concn;

ng/ml (minimum; maximum)Median concn; ng/ml(minimum; maximum)

Concn in plasma 250 ng/ml(% of total)

After 1 wk (122) 472 (NQa; 2,359) 77.0 1,136 (NQ; 2,708) After 2 wk (88) 690 (NQ; 2,236) 84.1 1,411 (NQ; 3,488) After 3 wk (55) 961 (59; 3,069) 87.3 1,694 (NQ; 4,108) After 4 wk (30) 1,225 (NQ; 3,460) 86.7 2,018 (NQ; 4,207)After 4 wk (25) 1,957 (193; 5,165) 96.0 2,677 (695; 6,762)

a NQ, not quantifiable.



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DISCUSSION

The current trial was set up to establish the potential role ofthe broad-spectrum azole antifungal itraconazole in preventingfungal infections in patients with a hematological malignancy

including autologous bone marrow transplant patients ex-pected to be neutropenic for at least 14 days. Attitudes towardsantifungal prophylaxis are different between countries and be-tween centers. As a remnant of the gastrointestinal decontam-ination approach, the still widely used oral nonabsorbableagent amphotericin B was selected as the comparative agent.

Collection of adequately documented fungal end point datahas been recognized as a serious difficulty for prophylacticevaluation, since confirmation is often obtained only after ini-tiation of intravenous amphotericin B or at autopsy. Therefore,the 4-week postprophylaxis visit was considered essential tocollect additional postprophylaxis evidence of suspected anddeep fungal infection. An overall and blinded assessment bythe Expert Committee harmonized the interpretation for alimited number of difficult cases.

The incidences of aspergillosis (1.8%) and proven deep fun-gal infection (2.8%, including invasive aspergillosis) observedin the itraconazole recipients were very similar to those ob-served previously. In two large prophylactic trials with itracon-azole in neutropenic patients (9, 10), Aspergillus infection hasbeen reported in 0 and 2% and proven deep fungal infectionshave been reported in 0.5 and 2.5% of the itraconazole-treatedpatients, respectively. In the present and both previous trialscombined, a clinically relevant reduction in the number ofcases of deep fungal infection including Aspergillus infectionwas obtained in favor of itraconazole oral solution comparedwith the use of oral amphotericin B, placebo, and fluconazole

(14 versus 28 cases, respectively). Related to this observation isthe number of patients dying with proven deep fungal infec-tions, mostly aspergillosis: 2 in the itraconazole arms versus 14in the comparative arms (oral amphotericin B, n 5; placebo,n 5; and fluconazole, n 4). Based on the blinded interim

analysis, it became evident that the required number of docu-mented cases of aspergillosis in the present trial could not beobtained by recruiting all patients as stipulated in the samplesize calculation. Statistical conclusions on very small incidencesare difficult to interpret. The majority of the patient populationin this trial mainly consisted of neutropenic patients with alower risk for mold infections. The risk for aspergillosis ishigher for patients undergoing allogeneic bone marrow trans-plantation, for patients with acute myeloid leukemia in secondrelapse, or patients with graft-versus-host disease treated withhigh-dose steroids. Only a few high-risk patients were includedin this study.

All cases of invasive aspergillosis were identified in France,except for one in the itraconazole group, which was observed in

The Netherlands. An explanation for the difference could bethat the incidence of aspergillosis varies strongly between dif-ferent hospitals, even in the same country. Furthermore, 46%of the total patient sample was recruited in France (129 of 281patients in the itraconazole group and 125 of 276 patients inthe oral amphotericin B group).

As expected from the trial comparison versus amphotericinB capsules, a statistically significant (P 0.004) higher inci-dence of superficial candidosis, mainly oropharyngeal candido-sis, was documented. Also, for itraconazole oral solution, which is effective in the treatment of oral and esophagealcandidosis (5), this effect is not surprising. The clinical relevance is, however, less clear. A significant relationship withdeep candidosis could not be established in this trial. Theadministration of empiric or therapeutic intravenous ampho-

tericin B is preferably to be avoided due to the potential ofsevere renal toxicity and other adverse experience. In the itra-conazole oral solution arm of the trial, the instantaneous riskof administration of intravenous amphotericin B was 33%lower than that in the oral amphotericin B arm. This difference was marginally statistically significant (P 0.052) and is con-sidered to be of clinical relevance. More than in therapeutictrials, the safety evaluation of a proposed drug for prophylaxisis very important. Interpreting safety aspects of one compo-nent of a multidrug regimen in highly immunocompromisedpatients is difficult. Even though HPCD was also used in theplacebo formulation, the double-blind, double-placebo designof the trial and the standard methodology to evaluate adverseevents and to classify biochemical parameters have been in-strumental in this assessment.

FIG. 2. Most frequently reported adverse events for the patients in this studytreated with itraconazole (Itr) or amphotericin B (Ampho B).

TABLE 5. Kind and incidence of fungal postprophylaxis end points according to the classificationof the Expert Committee for eligible patients

Eligible patient analysis parameteraNo. % of patients with end point posttreatment

Pb

Itraconazole (n 201) Amphotericin B (n 186)

Invasive aspergillosis 5 (2.5)c 9 (4.8)d 0.216Proven deep fungal infection (including invasive aspergillosis) 8 (4.0)c 12 (6.5)e 0.273

Superficial fungal infection 2 (1.0) 11 (5.9) 0.007Total proven fungal infection 10 (5.0) 23 (12.4) 0.009Suspected deep fungal infection (including fever of unknown origin) 75 (37.3) 73 (39.2) 0.696

a Patients were classified as eligible with a neutrophil count of0.5 109 /liter for at least 14 days.b Intergroup comparison, chi-square test.c One died.d Four died.e Five died.



7/7

In general, treatment with the itraconazole oral solution iswell tolerated (11). Any diarrhea induced by treatment withitraconazole oral solution is most likely due to the HPCDcarrier, which is known to induce soft stools and diarrhea froma daily dose of 16 g onwards. This dose was administered in theplacebo as well as in the active formulation. However, nauseaand vomiting, which both belong to the adverse event profile of

both itraconazole capsules and oral solution, did occur to sim-ilar extents in both groups. In the population studied, theoverall reporting of gastrointestinal adverse events mirrors theclinical day-by-day observations which occur independent of aclinical trial setting. Other adverse events for itraconazole arerashes, transient increases in liver function tests, and hypoka-lemia, but again, no relevant differences were observed.

Biochemistry abnormalities are inherent in the patient pop-ulation studied. All observed increases and decreases weresimilar in both groups, pointing at the background laboratoryabnormalities in this population. The hypokalemia confirmedfindings in the adverse event analysis.

In conclusion, prophylactic administration of itraconazoleoral solution at 5 mg/kg daily in patients with hematologicalmalignancies and neutropenia significantly reduced the inci-dence of superficial fungal infections. The number of systemicfungal infections, the number of deaths due to proven deepfungal infections, the incidence of administration of systemicantifungals, and the time prior to this administration wereinfluenced positively by the administration of itraconazole oralsolution.

ACKNOWLEDGMENTS

We are indebted to our patients and health care professionals at various medical centers, without whose willing participation this trial would not have been possible. We thank the following additionalparticipants in the trial: in Austria, M. Eibl and P. Neumeister (Mediz-inische Universitatsklinik, Graz); D. Lutz and M. Girschikofsky(KH. D. Elisabethinen, Linz); and P. Kalhs (AKH, Vienna); in France,G. Auzanneau, T. De Revel, and G. Nedellec (Hopital du Val deGrace, Paris); J. Abgrall, C. Berthou, and L. Sensebe (CHU Morvan,Brest); F. Dreyfus and D. Bouscary (LHopital Cochin, Paris); D.Caillot (CHU Hopital denfants, Dijon); D. Fiere, C. Cartel, and J.Trency (CHU Edouard Herriot, Lyon); C. Martin and B. Corront(Centre Hospitalier dAnnessy, Annecy); J. Cahn and E. De Coninck(CHU de Besancon, Besancon); B. Desablens (CHU dAmiens,

Amiens); H. Dombret and S. Glaisner (Hopital Saint-L ouis, Paris); J.Rossi and N. Fegueux (Hopital Lapeyronie, Montpellier); J. Pico andC. Fuertes (Institut Gustave Roussey, Villejuif); F. Guilhot and E.Randriamalala (Centre Hospitalier Universitaire, Poitiers); A. Stoppa(Institut Paoli, Calmettes, Marseille); R. Zittoun and A. Vekhoff (Ho-pital Dieu, Paris); J. Sotto and F. Viret (CHU Grenoble, Grenoble); B.Witz (Hopital de Brabois, Nancy); R. Hebrecht (Hopital Hautepierre,Strasbourg); J. Pris and F. Huguet (Hopital Purpan, Toulouse); A.Najman and F. Isnard (Hopital Saint-Antoine, Paris); V. Leblond, C.Soussain, and H. Zouabi (Hopital Pitie-Salpetriere, Paris); O. Lertho-

lary (Hopital Avicenne, Bobigny); J. Sotto and L. Melina (HopitalMichallon, Grenoble); D. Guyetat and P. Criel (Hopital Nord, SaintEtienne); B. Pignon (CHU de Reims, Reims); H. Leporrier and O.Reman (Hopital Clemenceau, Caen); and M. Renoux (Hopital deBayonne, Bayonne); in Greece, H. Bassaris (Pathologic Clinic, Rio-Patras); G. Petrikkos (Laiko General Hospital of Athens, Athens); andB. Seitanidis (Metaxa Hospital, Athens); in Portugal, (F. Campilho, A.Junior, and P. Pimentel (Instituto Portugues de Oncologia, Porto); J.Fernandes (Hospital dos Capuchos, Lisbon); F. Principe and C.Granato (Hospital de Sao Joao, Porto); and P. Garcia and I. Sousa(Hospital da Universidade de Coimbra, Coimbra); in Spain, F. Her-nandez, M. Alvarez, M. Canales, M. Jimenez, V. Jimenez, A. Lafuente,M. Martin, P. Matecs, M. Merado, M. Rodriguez, and J. Sevilla (Hos-pital La Paz, Madrid); J. San Miguel, C. Canizo, and L. Vazquez(Hospital Universitario de Salamanca, F. Cobo and E. Montserrat(Hospital Clnic IDIBAPS, Barcelona); A. Rodriguez Noriega, C.

Grande, and M. Lizascain (Hospital 12 de Octubre, Madrid); and M.Sanz and I. Jarque (Hospital La Fe, Valencia); and in The Nether-lands, B. Daenen (Academisch Ziekenhuis Groningen, Groningin); B.De Pauw (Sint-Radboud Ziekenhuis, Nijmegen); W. Gerrits (Zieken-huis Leyenburg, Amsterdam); and J. Van der Lelie (Academic Med-ical Center, Amsterdam).

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