Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Invasive Pulmonary Aspergillosis, Lymphoblastic Leukaemia, Myeloblastic Leukaemia, Lymphoblastic Leukemia, Myeloblastic Leukemia

Intervention / Treatment
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* Drug: AMPHOTERICIN B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: patients between 3 and 18 years. Diagnosis of myeloblastic or lymphoblastic AL during intensive chemotherapy. Informed consent of parents/guardians and/or assent of the patient has been obtained. Exclusion Criteria: Probable or proven invasive pulmonary fungal infection before entering the trial. Previous chronic renal impairment or baseline serum creatinine > 2.5 mg /dL Severe hepatic impairment. Moderate-severe asthma being treated pharmacologically. Antifungal treatment for filamentous fungi in the last 4 weeks. Participating or have participated in a clinical trial during the last 4 weeks. Mentally retarded Known allergy or hypersensitivity to the active ingredient of the study drug or to any of its excipients. 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. Pregnancy (in women of fertile age). 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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amphotericin B (ABELCET®)<br>Drug: AMPHOTERICIN B Dosage form: Abelcet® 5mg/ml administered by inhalation. Dosage: 10 ml (50 mg) for the first week with a frequency twice a week. Dosage: from the second week onwards 5 ml (25 mg) with a frequency of a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3. Duration: 4-5 prophylaxis courses defined as each administration period during a neutropenia period, with a 4-6 weeks length considering the duration of neutropenia. | Drug: AMPHOTERICIN B<br>* The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.<br>* Other names: Abelcet® 5 mg/ml;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability | is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each). | at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis | The incidence of invasive pulmonary aspergillosis during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with invasive pulmonary aspergillosis and the number of paediatric patients on prophylaxis with Acute Leukaemia (AL) undergoing intensive chemotherapy. | at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks | 
| Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®. | Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy. | at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive pulmonary aspergillosis, IFI, Leukaemia, Leukemia, Pediatric, Paediatrics, Amphotericin B, Aspergillosis, Pulmonary Aspergillosis, Invasive Aspergillosis, Antifungal agents, Fungal infections, Invasive Fungal Infection