Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis

This study has been completed.
Sponsor:
Collaborators:
Gilead Sciences
Nexstar Pharmaceuticals
Information provided by:
Erasmus Medical Center
ClinicalTrials.gov Identifier:
NCT00263315
First received: December 7, 2005
Last updated: August 17, 2006
Last verified: August 2006
  Purpose

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 Intervention Phase
Aspergillosis
Drug: nebulised liposomal amphotericin B
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
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.

Resource links provided by NLM:


Further study details as provided by Erasmus Medical Center:

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

Secondary Outcome Measures:
  • 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

Estimated Enrollment: 320
Study Start Date: January 2000
Estimated Study Completion Date: May 2006
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00263315

Locations
Netherlands
Erasmus MC centrumlocatie
Rotterdam, Netherlands
Erasmus MC locatie Daniel den Hoed
Rotterdam, Netherlands
Sponsors and Collaborators
Erasmus Medical Center
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
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00263315     History of Changes
Other Study ID Numbers: METC 191.137/2000/088
Study First Received: December 7, 2005
Last Updated: August 17, 2006
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Erasmus Medical Center:
aspergillosis
mycosis
neutropenia
primary prevention
hematologic diseases
amphotericin B
AmBisome
liposomal amphotericin B

Additional relevant MeSH terms:
Aspergillosis
Invasive Pulmonary Aspergillosis
Dermatomycoses
Hyalohyphomycosis
Infection
Lung Diseases
Lung Diseases, Fungal
Mycoses
Pulmonary Aspergillosis
Respiratory Tract Diseases
Skin Diseases
Skin Diseases, Infectious
Amphotericin B
Liposomal amphotericin B
Amebicides
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents
Antiparasitic Agents
Antiprotozoal Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014