Clinical trial NCT01615809: Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia
Official title: A Phase II Trial to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Invasive Pulmonary Aspergillosis
Lymphoblastic Leukaemia
Myeloblastic Leukaemia
Lymphoblastic Leukemia
Myeloblastic Leukemia
Keywords: Invasive pulmonary aspergillosis
IFI
Leukaemia
Leukemia
Pediatric
Paediatrics
Amphotericin B
Aspergillosis
Pulmonary Aspergillosis
Invasive Aspergillosis
Antifungal agents
Fungal infections
Invasive Fungal Infection
Lead sponsor: Fundació Sant Joan de Déu
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Spain
First posted: 2012-06-11
Enrollment: 32
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive chemotherapy.

Detailed description: In recent years the incidence of invasive fungal infection (IFI) especially when caused by filamentous fungi has increased in patients with haematological malignancies and there exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic progress, invasive aspergillosis remains a major clinical problem of haematological patients, given the still high mortality rates and the huge economic cost of hospitalization of patients, which is attributable to aspergillosis. In addition to the morbidity and mortality rates, these infections interfere with the chemotherapy treatment plan with the risk of compromising the outcome of the antileukemic treatment.

In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in haematological patients, however it was not effective in a large multicenter study with neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade. During this time the use of azole agents as drugs of choice for antifungal prophylaxis in high risk patients was consolidated. However, one of the main problems in the use of triazoles with activity against filamentous fungi (itraconazole, voriconazole, posaconazole) is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the most serious interactions is that which occurs with vincristine, used throughout the treatment of acute lymphoblastic leukemia, and which has lead to reports of neurotoxicity due to metabolic inhibition.

ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.

Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal infections in adult patients. Although it has a pediatric indication, there are numerous studies published regarding the safety levels of Abelcet® administered intravenously in children and in haematological adults patients which look very promising. In this context, the working hypothesis proposed in this project is that the administration of aerosolised ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

In the treatment of pediatric patients with haematological malignancies the use of intensive chemotherapy is required, which is immunosuppressive and therefore significantly increases the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (\>50%) in those patients, making it imperative to adopt effective, preventive, prophylactic measures. Drug interactions occur frequently with triazole antifungal drugs; cases of clinically significant interactions with vincristine, an anchor drug in the treatment of the majority of pediatric leukemia, are documented. On the other hand, there are promising data from previous studies regarding the safety and efficacy of the intravenous ABLC formulation (Abelcet®) in the treatment of pediatric patients with fungal infections.

If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an effective, safe and reliable prophylactic option for IPA. It would offer an alternative to the systemic administration of antifungal triazoles without affecting the antileukemic treatment in pediatric patients with AL.

Eligibility criteria: Inclusion Criteria:

1. Age: patients between 3 and 18 years.
2. Diagnosis of myeloblastic or lymphoblastic AL during intensive chemotherapy.
3. Informed consent of parents/guardians and/or assent of the patient has been obtained.

Exclusion Criteria:

1. Probable or proven invasive pulmonary fungal infection before entering the trial.
2. Previous chronic renal impairment or baseline serum creatinine \> 2.5 mg /dL
3. Severe hepatic impairment.
4. Moderate-severe asthma being treated pharmacologically.
5. Antifungal treatment for filamentous fungi in the last 4 weeks.
6. Participating or have participated in a clinical trial during the last 4 weeks.
7. Mentally retarded
8. Known allergy or hypersensitivity to the active ingredient of the study drug or to any of its excipients.
9. Any serious concomitant disease that in the investigator's opinion could compromise the completion of the trial or affect the patient's tolerability to this treatment.
10. Pregnancy (in women of fertile age).
11. Breast-feeding.

Patients are defined as having probable IFI when their radiological image is suggestive of fungal infection and they have positive antigenemia for Aspergillus. IFI would be proven when the presence of Aspergillus is confirmed in aspirate culture or by lung biopsy.

Primary outcomes:
measure: Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability
timeFrame: at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks
Secondary outcomes:
measure: Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis
timeFrame: at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks
measure: Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®.
timeFrame: at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks
Other outcomes:
Locations:
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Déu
state: Barcelona
Study officials:
affiliation: Hospital Sant Joan de Deu
name: Jesus Estella, PhMD
role: PRINCIPAL_INVESTIGATOR
References:
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