Amphotericin B liposomal clinical studies

# Description of Clinical Studies
Eleven clinical studies supporting the efficacy and safety of AmBisome were conducted. This clinical program included both controlled and uncontrolled studies. These studies, which involved 2171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis.
Nineteen hundred and forty-six episodes were evaluable for efficacy, of which 1280 (302 pediatric and 978 adults) were treated with AmBisome.
Three controlled empirical therapy trials compared the efficacy and safety of AmBisome to amphotericin B. One of these studies was conducted in a pediatric population, one in adults, and a third in patients aged 2 years or more. In addition, a controlled empirical therapy trial comparing the safety of AmBisome to Abelcet (amphotericin B lipid complex) was conducted in patients aged 2 years or more.
One controlled trial compared the efficacy and safety of AmBisome to amphotericin B in HIV patients with cryptococcal meningitis.
One compassionate use study enrolled patients who had failed amphotericin B deoxycholate therapy or who were unable to receive amphotericin B deoxycholate because of renal insufficiency.

## Empirical Therapy in Febrile Neutropenic Patients
Study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome (1.5-6 mg/kg/day) compared with amphotericin B deoxycholate (0.3-1.2 mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. Therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7 days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection.
The overall therapeutic success rates for AmBisome and the amphotericin B deoxycholate were equivalent. Results are summarized in the following table.
Note: The categories presented below are not mutually exclusive.
This therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocyte colony stimulating factor.
The incidence of mycologically confirmed and clinically diagnosed, emergent fungal infections are presented in the following table. AmBisome and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections.
Mycologically confirmed fungal infections at study-entry were cured in 8 of 11 patients in the AmBisome group and 7 of 10 in the amphotericin B group.
Study 97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of AmBisome (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six patients received AmBisome (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy, and in fact, Abelcet is not labeled for this indication.
Two supportive prospective randomized, open label, comparative multi-center studies examined the efficacy of two dosages of AmBisome (1 and 3 mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease. Study 104-10 enrolled adult patients (n=134). Study 104-14 enrolled pediatric patients (n=214). Both studies support the efficacy equivalence of AmBisome and amphotericin B as empirical therapy in febrile neutropenic patients.

## Treatment of Cryptococcal Meningitis in HIV Infected Patients
Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of AmBisome at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received AmBisome 3 mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76 patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14  4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for AmBisome and amphotericin B deoxycholate are summarized in the following table:
Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of AmBisome 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that AmBisome 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study.
The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving AmBisome compared to amphotericin B deoxycholate; therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen.

## Treatment of Patients with Aspergillus Species, Candida Species and/or Cryptococcus Species Infections Refractory to Amphotericin B Deoxycholate, or in Patients Where Renal Impairment or Unacceptable Toxicity Precludes the Use of Amphotericin B Deoxycholate
AmBisome was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis.

## Treatment of Visceral Leishmaniasis
AmBisome was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum. Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi.
AmBisome achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12-30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30-40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients:
When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of AmBisome or of maintenance therapy with this drug among immunocompromised patients.