Table 2.
Summary of Pivotal Randomized, Clinical Trials Demonstrating Efficacy and Safety of Liposomal Amphotericin B in Treatment and Prevention of Invasive Fungal Diseases
| Study/Design | Endpoints of Efficacy | Main Results |
|---|---|---|
| Proven or probable invasive aspergillosis | ||
| Open-label, randomized, multicenter trial comparing the efficacy of 2 doses of LAmB (1 and 4 mg/kg/day) for the treatment of proven or probable invasive aspergillosis in 120 neutropenic patients [39]. | Complete/partial responses and stable disease at end of therapy in patients receiving ≥1 dose; overall mortality at 2 months after start of therapy. | Response rates were 64% in the 41 eligible LAmB 1 mg/kg/day recipients and 48% in the 46 eligible LAmB 4 mg/kg/day recipients; overall, mortality was 42% and 49% in the 2 cohorts, respectively. The rate of patients with AEs was slightly higher in the LAmB 4 mg/kg/day cohort. |
| Double-blind, randomized, multicenter trial in 201 patients with proven or probable invasive mold infection, comparing LAmB as first-line therapy at either 3 or 10 mg/kg/day for 14 days, followed by 3 mg/kg/day [40]. | Complete or partial response at the end of study drug treatment in patients receiving ≥1 dose. Overall mortality at 12 weeks after start of therapy. | A complete or partial response was achieved in 50% and 46% of patients in the 3 and 10 mg/kg/day groups, respectively. Mortality at 12 weeks was 28% and 41% in the 3 and 10 mg/kg/day arms, respectively. The rates of nephrotoxicity and hypokalemia were significantly higher in the high-dose group. |
| Invasive Candida infections | ||
| Double-blind, randomized, multicenter, non-inferiority trial comparing the efficacy of LAmB (3 mg/kg/day) and micafungin (100 mg/day) as first-line treatment of candidemia and invasive candidiasis in 531 patients [41]. | Clinical (complete or partial resolution of symptoms) and mycological (eradication or presumed eradication) response at the end of treatment in the per protocol analysis. | Treatment success was observed for 170 patients (89.5%) treated with LAmB and 181 patients (89.6%) treated with micafungin. Efficacy was independent of the Candida species, site of infection, neutropenic status, APACHE II score, and catheter removal/replacement. Fewer treatment-related AEs and discontinuations were observed with micafungin. |
| Cryptococcal meningoencephalitis | ||
| Double-blind, randomized, multicenter trial comparing efficacy and safety of LAmB at either 3 or 6 mg/kg/day to DAmB at 0.7 mg/kg/day in 267 patients with AIDS and acute cryptococcal meningitis [42]. | Mycological success (conversion of cerebrospinal fluid culture results) at Week 2 (14 ± 4 days), protocol-defined therapeutic success at Week 10, and survival at Week 10 among the modified intent-to-treat population. | Efficacy was similar among all 3 treatment groups; overall mortality at 10 weeks was 11.6%, with no significant differences among treatment groups. Infusion-related reactions were significantly less frequent in LAmB-treated patients and fewer patients receiving the 3 mg/kg/day dose of LAmB developed a doubling of the serum creatinine value. |
| Disseminated histoplasmosis | ||
| Double-blind, randomized, multicenter trial comparing LAmB at 3 mg/kg/day with DAmB at 0.7 mg/kg/day for 2 weeks in 81 patients with AIDS and moderate-to-severe disseminated histoplasmosis [43]. | Clinical success, conversion of baseline blood cultures to negative, survival during induction therapy, and acute toxicities that necessitated discontinuation of treatment. | Clinical success was achieved in 45/51 patients (88%) receiving LAmB and 14/22 patients (64%) treated with DAmB (P = .014). Culture conversion rates were similar. Fewer patients receiving LAmB died during induction (P = .04). Infusion-related side effects and nephrotoxicity were less frequent in patients treated with LAmB (25% vs 63% and 9% vs 37%; P = .002 and P = .003, respectively). |
| Empirical therapy in patients with fever and neutropenia | ||
| Combined analysis of 2 randomized, multicenter trials comparing LAmB at 1 or 3 mg/kg/day with DAmB at 1 mg/kg/day in a total of 338 adult and pediatric patients with fever and neutropenia who were not responding to broad-spectrum antibacterial treatment [38]. | Clinical success, defined by a minimum of 3 consecutive days with fever <38°C, continuing to study end (recovery of neutrophils to 0.5 × 109/L). Addition of systemic antifungals, development of systemic fungal infection, and persistent fever to study end were considered treatment failures. | Similar success rates in patients treated with LAmB (58% and 64%) and DAmB (49%), but fewer drug-related adverse effects and severe drug-related adverse effects with LAmB (P < .01). Nephrotoxicity, defined as doubling of the serum creatinine value from baseline, was less frequent in the LAmB arms versus DAmB (0% and 3%, respectively, vs 23%), as was hypokalemia (P < .01). |
| Double-blind, randomized, multicenter trial to compare LAmB at 3 mg/kg/day with DAmB at 0.6 mg/kg/day in a total of 687 adult and pediatric patients with fever and neutropenia who were not responding to broad-spectrum antibacterial treatment [44]. | Composite of 5 criteria: survival for 7 days after initiation of the study drug; resolution of fever during the period of neutropenia; successful treatment of any baseline fungal infection; the absence of breakthrough fungal infections during administration of the study drug or within 7 days after the end of treatment; and absence of premature discontinuation of the study drug because of toxicity or lack of efficacy. | The composite rates of successful treatment were similar (50% for LAmB and 49% for DAmB), as were survival rates (93% and 90%, respectively), resolution of fever (58% and 58%, respectively), and premature discontinuation of the study drug (14% and 19%, respectively). Fewer proved breakthrough fungal infections were observed in the LAmB group (3.2% vs 7.8%, respectively; P = .009). LAmB was associated with significantly fewer infusion-related reactions and fewer patients developed a serum creatinine level 2 times the upper limit of normal (19% vs 34%, respectively; P < .001). |
| Primary antifungal prophylaxis | ||
| Open-label, randomized, single-center trial of low-dose LAmB (50 mg every other day) versus no systemic antifungal therapy as antifungal prophylaxis in 219 neutropenic episodes in 132 patients with hematological malignancies and expected neutropenia for 10 days [45]. | Failure of antifungal prophylaxis, defined as occurrence of proven or probable invasive fungal diseases under prophylactic study treatment. Pneumonia without identification of a causative organism, mortality from any cause, and mortality related to invasive fungal disease were secondary endpoints. | In the first episode of each patient, the incidences of proven or probable invasive fungal diseases were 6.7% in LAmB-treated patients (5/75) and 35% in the control patients (20/57; P = .001). Invasive aspergillosis occurred less frequently in patients receiving LAmB (P = .0057). Pneumonia occurred in 6 vs 28 neutropenic episodes (P < .001), and there was no difference in overall and fungal-related mortality. |
| Double-blind, randomized, placebo-controlled trial of LAmB (2.5 mL of a 5 mg/mL solution) versus placebo inhalation twice a week in 271 adult patients with hematological disease with expected neutropenia for 10 days, studied during 407 neutropenic episodes [46]. | Occurrence of proven or probable invasive pulmonary aspergillosis, according to the European Organization for Research and the Treatment of Cancer/Mycoses Study Group definitions. Other endpoints were overall mortality and fungal infection-related mortality. |
There were 18/132 patients in the placebo group versus 6/139 patients in the LAmB group who developed invasive pulmonary aspergillosis (odds ratio 0.26, 95% confidence interval 0.09–0.72; P = .005). There was no difference in overall and infection-related mortality rates. More patients in the LAmB group versus the placebo group discontinued the inhalation therapy for at least 1 week (45% vs 30%, respectively; P = .01). |
| Double-blind, randomized, multicenter trial to compare prophylactic LAmB at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment in 355 adult patients undergoing remission induction therapy for acute lymphoblastic leukemia [47]. | Development of proven or probable invasive fungal diseases. Secondary endpoints included those focused on the safety and tolerability of prophylactic LAmB. | Rates of proven and probable invasive fungal diseases were 7.9% (18/228) in the LAmB group and 11.7% (13/111) in the placebo group (P = .24). Overall mortality rates were similar between the groups: 7.2% (17/237) for LAmB and 6.8% (8/118) for placebo. There were no differences in premature, treatment-related discontinuations. Hypokalemia and creatinine increase were significantly more frequent with LAmB (P < .001). |
Please note the differences in disease definitions and outcome assessment across clinical trials.
Abbreviations: AE, adverse event; AIDS, acquired immunodeficiency syndrome; APACHE, Acute Physiology and Chronic Health Evaluation; DAmB, deoxycholate amphotericin B; LAmB, liposomal amphotericin B.