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Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00263315
Recruitment Status : Completed
First Posted : December 8, 2005
Last Update Posted : August 18, 2006
Gilead Sciences
Nexstar Pharmaceuticals
Information provided by:
Erasmus Medical Center

Brief 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.

Condition or disease Intervention/treatment Phase
Aspergillosis Drug: nebulised liposomal amphotericin B Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Prevention
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.
Study Start Date : January 2000
Study Completion Date : May 2006

Primary Outcome Measures :
  1. SAFETY: Discontinuation for >1week due to intolerance
  2. EFFICACY: Proven/probable invasive pulmonary aspergillosis

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

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00263315

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Erasmus MC centrumlocatie
Rotterdam, Netherlands
Erasmus MC locatie Daniel den Hoed
Rotterdam, Netherlands
Sponsors and Collaborators
Erasmus Medical Center
Gilead Sciences
Nexstar Pharmaceuticals
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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

Additional Information:
Layout table for additonal information Identifier: NCT00263315     History of Changes
Other Study ID Numbers: METC 191.137/2000/088
First Posted: December 8, 2005    Key Record Dates
Last Update Posted: August 18, 2006
Last Verified: August 2006
Keywords provided by Erasmus Medical Center:
primary prevention
hematologic diseases
amphotericin B
liposomal amphotericin B
Additional relevant MeSH terms:
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Amphotericin B
Liposomal amphotericin B
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Anti-Bacterial Agents
Antifungal Agents