Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis

Nebulized Liposomal Amphotericin B (Ambisome) Versus Nebulized Placebo for the Prophylaxis of Invasive Pulmonary Aspergillosis in Haematological Patients With Prolonged Neutropenia. A Randomized Clinical Trial.

A Phase II/III randomized double-blind study comparing the safety and the efficacy of a weekly administration of 25 mg nebulized AmBisome with nebulized placebo solution to prevent invasive pulmonary aspergillosis in neutropenic hemato-oncologic patients.

Study Overview

• Status: Completed
• Conditions: Aspergillosis
• Intervention / Treatment: Drug: nebulised liposomal amphotericin B

Detailed Description

The morbidity, mortality and costs of invasive pulmonary aspergillosis (IPA) in neutropenic patients are high. An effective intervention to prevent IPA would therefore be welcome. The incidence of IPA in neutropenic hematology patients in our institution was recently estimated to be 5-10%. Currently, only HEPA filtration is routinely used for the prevention of IPA. In 1988, Schmitt et al. showed a significant delayed mortality in rat model of IPA when rats were treated with aerosolized conventional amphotericin-B (amB) two days before infection (1). Conventional amB may interfere with surfactant function in the lungs. In contrast, liposomal amphotericin-B contains phospholipids that are structurally related to surfactant and inhibits natural surfactant function only slightly. Furthermore, in rats, mean concentrations of AmB in lungs were 3.7 times higher at day one and almost 6 times higher at day seven after a single dose treatment with aerosolized liposomal amB when compared with conventional AmB (2). Only one non-placebo controlled randomized clinical trial evaluated the prophylactic use of inhalation therapy with conventional amB for the prevention of IPA and a non-significant 43% reduction was observed (3). We postulate that the weekly inhalation of liposomal AmB in neutropenic hematology patients can prevent IPA.

In this randomised placebo controlled clinical trial we compare the safety and efficacy of the administration of nebulized liposomal AmB (2x/week) with placebo for the prevention of IPA in haematological patients with an expected duration of neutropenia of >10d. To demonstrate a reduction in incidence of invasive pulmonary aspergillosis from 7% to 1%, a total of 170 neutropenic episodes in each arm will be included (power 80%, two-tailed alfa=0.05). The primary efficacy endpoint is the cumulative percentage of patients developing a proven or probable IPA. Per protocol serum galactomannan levels are monitored 2x/week and a HR-CT of the lungs will be performed for unexplained fever (>5d) unresponsive to broad-spectrum antibiotic therapy. EORTC/MSG criteria are used for diagnosis of IPA. The primary safety endpoint is a premature discontinuation of the study drug for >1week due to intolerance.

• Study Type: Interventional
• Enrollment: 320
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Erasmus MC centrumlocatie
  • Rotterdam, Netherlands
    • Erasmus MC locatie Daniel den Hoed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female hospitalized patients aged > 18 yr
2. The patient has a hematologic malignancy or will receive a bone-marrow transplant
3. The patient starts with a course of chemotherapy within 4 days or is already neutropenic at admission
4. The expected duration of severe neutropenia (PMN<0.5x10*9/L) following study entry is > 10 days
5. The patient is receiving oral antibiotic prophylaxis and fluconazole
6. Written informed consent has been obtained

Exclusion Criteria:

1. The patient shows evidence of a pulmonary fungal infection or a fungal sinusitis at trial entry
2. The concomitant use of systemic anti-aspergillus treatment such as itraconazole or any intravenous formulation of amphotericin B at study entry
3. Known hypersensitivity to amphotericin B
4. Any evidence of pneumonia or pneumonitis at trial entry
5. Any impossibility to use a nebulizer properly
6. Expected survival < 3 months at entry
7. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
SAFETY: Discontinuation for >1week due to intolerance
EFFICACY: Proven/probable invasive pulmonary aspergillosis

Secondary Outcome Measures

Outcome Measure
SAFETY STUDY:
A probably or definitely related AE of the respiratory tract (CTC grade > 2)
Any probably or definitely related AE by type and severity (CTC grade > 2)
Requirement of pre-medication to tolerate nebulization of the study drug
Spirometric changes after inhalation
EFFICACY STUDY:
Proven, probable or possible invasive pulmonary aspergillosis
A confirmed positive serum galactomannan concentration of 0.5 ng/ml or more
The use of systemic antifungal drugs (days) during the neutropenic episodes
The number of days of fever of unknown origin during neutropenia
Mortality due to a pulmonary fungal infection

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Gilead Sciences; Nexstar Pharmaceuticals
• Investigators: Principal Investigator: Bart JA Rijnders, MD, PhD, Erasmus MC; Principal Investigator: Siem de Marie, MD, PhD, Erasmus MC; Principal Investigator: Jan J Cornelissen, MD, PhD, Erasmus MC; Principal Investigator: Lennert Slobbe, MD, Erasmus MC; Principal Investigator: A Vulto, PhD, Erasmus MC; Principal Investigator: M J Becker, PhD, Erasmus MC

Publications and helpful links

General Publications

• Cicogna CE, White MH, Bernard EM, Ishimura T, Sun M, Tong WP, Armstrong D. Efficacy of prophylactic aerosol amphotericin B lipid complex in a rat model of pulmonary aspergillosis. Antimicrob Agents Chemother. 1997 Feb;41(2):259-61. doi: 10.1128/AAC.41.2.259.
• Schwartz S, Behre G, Heinemann V, Wandt H, Schilling E, Arning M, Trittin A, Kern WV, Boenisch O, Bosse D, Lenz K, Ludwig WD, Hiddemann W, Siegert W, Beyer J. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood. 1999 Jun 1;93(11):3654-61.
• Schmitt HJ, Bernard EM, Andrade J, Edwards F, Schmitt B, Armstrong D. MIC and fungicidal activity of terbinafine against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother. 1988 May;32(5):780-1. doi: 10.1128/AAC.32.5.780.

Helpful Links

• Erasmus Medical Center website

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Study Completion: May 1, 2006

Study Registration Dates

• First Submitted: December 7, 2005
• First Submitted That Met QC Criteria: December 7, 2005
• First Posted (Estimate): December 8, 2005

Study Record Updates

• Last Update Posted (Estimate): August 18, 2006
• Last Update Submitted That Met QC Criteria: August 17, 2006
• Last Verified: August 1, 2006

More Information

Terms related to this study

• Keywords: neutropenia; aspergillosis; primary prevention; hematologic diseases; AmBisome; amphotericin B; mycosis; liposomal amphotericin B
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Aspergillosis; Anti-Infective Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: METC 191.137/2000/088