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Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis

NCT ID: NCT00263315

Last Updated: 2006-08-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

320 participants

Study Classification

INTERVENTIONAL

Study Start Date

2000-01-31

Study Completion Date

2006-05-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Aspergillosis

Keywords

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aspergillosis mycosis neutropenia primary prevention hematologic diseases amphotericin B AmBisome liposomal amphotericin B

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

DOUBLE

Interventions

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nebulised liposomal amphotericin B

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Gilead Sciences

INDUSTRY

Sponsor Role collaborator

Nexstar Pharmaceuticals

INDUSTRY

Sponsor Role collaborator

Erasmus Medical Center

OTHER

Sponsor Role lead

Principal Investigators

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Bart JA Rijnders, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Siem de Marie, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Jan J Cornelissen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Lennert Slobbe, MD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

A Vulto, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

M J Becker, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Locations

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Erasmus MC centrumlocatie

Rotterdam, , Netherlands

Site Status

Erasmus MC locatie Daniel den Hoed

Rotterdam, , Netherlands

Site Status

Countries

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Netherlands

References

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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.

Reference Type BACKGROUND
PMID: 3134851 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 9021176 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10339471 (View on PubMed)

Related Links

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http://www.erasmusmc.nl

Erasmus Medical Center website

Other Identifiers

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METC 191.137/2000/088

Identifier Type: -

Identifier Source: org_study_id