Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis

Aspergillosis Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00263315
• Other study ID #: METC 191.137/2000/088
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: December 7, 2005
• Last updated: August 17, 2006
• Start date: January 2000
• Est. completion date: May 2006

Study information

• Verified date: August 2006
• Source: Erasmus Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 320
• Est. completion date: May 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Aspergillosis
• Invasive Pulmonary Aspergillosis

Intervention

Drug:
• nebulised liposomal amphotericin B

Locations

Country	Name	City	State
Netherlands	Erasmus MC centrumlocatie	Rotterdam
Netherlands	Erasmus MC locatie Daniel den Hoed	Rotterdam

Sponsors (3)

Lead Sponsor	Collaborator
Erasmus Medical Center	Gilead Sciences, Nexstar Pharmaceuticals

Country where clinical trial is conducted

Netherlands, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SAFETY: Discontinuation for >1week due to intolerance
Primary	EFFICACY: Proven/probable invasive pulmonary aspergillosis
Secondary	SAFETY STUDY:
Secondary	A probably or definitely related AE of the respiratory tract (CTC grade > 2)
Secondary	Any probably or definitely related AE by type and severity (CTC grade > 2)
Secondary	Requirement of pre-medication to tolerate nebulization of the study drug
Secondary	Spirometric changes after inhalation
Secondary	EFFICACY STUDY:
Secondary	Proven, probable or possible invasive pulmonary aspergillosis
Secondary	A confirmed positive serum galactomannan concentration of 0.5 ng/ml or more
Secondary	The use of systemic antifungal drugs (days) during the neutropenic episodes
Secondary	The number of days of fever of unknown origin during neutropenia
Secondary	Mortality due to a pulmonary fungal infection

External Links

•   Erasmus Medical Center website