Clinical trial NCT00263315: Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Aspergillosis
Keywords: aspergillosis
mycosis
neutropenia
primary prevention
hematologic diseases
amphotericin B
AmBisome
liposomal amphotericin B
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
name: Nexstar Pharmaceuticals
First posted: 2005-12-08
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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 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

Primary outcomes:
measure: SAFETY: Discontinuation for >1week due to intolerance
measure: EFFICACY: Proven/probable invasive pulmonary aspergillosis
Secondary outcomes:
measure: SAFETY STUDY:
measure: A probably or definitely related AE of the respiratory tract (CTC grade > 2)
measure: Any probably or definitely related AE by type and severity (CTC grade > 2)
measure: Requirement of pre-medication to tolerate nebulization of the study drug
measure: Spirometric changes after inhalation
measure: EFFICACY STUDY:
measure: Proven, probable or possible invasive pulmonary aspergillosis
measure: A confirmed positive serum galactomannan concentration of 0.5 ng/ml or more
measure: The use of systemic antifungal drugs (days) during the neutropenic episodes
measure: The number of days of fever of unknown origin during neutropenia
measure: Mortality due to a pulmonary fungal infection
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus MC centrumlocatie
city: Rotterdam
country: Netherlands
facility: Erasmus MC locatie Daniel den Hoed
Study officials:
affiliation: Erasmus Medical Center
name: Bart JA Rijnders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Siem de Marie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Jan J Cornelissen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Lennert Slobbe, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: A Vulto, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: M J Becker, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1128/AAC.32.5.780.
citation: 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.
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.