Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia
|First Received Date ICMJE||June 4, 2012|
|Last Updated Date||December 3, 2013|
|Start Date ICMJE||October 2011|
|Primary Completion Date||August 2013 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Number of Participants with Adverse Events that results in the interruption of treatment, as a Measure of Safety and Tolerability [ Time Frame: Baseline (week 1) and Last week of treatment (the number of the last week is variable by each patient, depending of the number of cicles needed by each patient) ] [ Designated as safety issue: Yes ]
The primary efficacy variable will be 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).
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01615809 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia|
|Official Title ICMJE||A Phase II CT 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.|
The aim of this clinical trial is to assess 25-30 patients of both sexes, between the ages of 3 to 18 years, who are receiving intensive chemotherapy treatment for acute myeloblastic or lymphoblastic leukemia (AML, ALL) and will be treated with aerosolised (inhalation) amphotericin B lipid complex (Abelcet®) as a prophylactic for invasive pulmonary aspergillosis during prolonged neutropenia.
The trial will evaluate the overall tolerability of the drug and the efficacy of aerosolised ABLC for primary prophylaxis of invasive pulmonary aspergillosis (IPA). In the event that the working hypothesis is confirmed, 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.
In recent years the incidence of IFI (invasive fungal infection) 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.
An infection caused by Aspergillus is usually acquired from inhalation of conidia. The lungs are the primary site of infection in most patients. In the 1990's the administration of aerosolised amphotericin B deoxycholate was evaluated as a prophylaxis of pulmonary fungal infections. 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. 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.
There are experiences in adult haematological patients which look very promising. For example, a non-comparative study in 27 subjects undergoing allogeneic HSCT (n=40) with nonmyeloablative conditioning, showed good tolerability and achieved an effective prophylaxis (IFI: 2.5%). The combined prophylactic regimen consisted of aerosolised ABLC (Abelcet®) 50 mg once daily for 4 days, then once weekly for 13 weeks, and associated with fluconazole 400 mg daily until day +100. The most relevant adverse events were not frequent (cough, nausea, taste disturbance, vomiting [10/428 administrations (2.2%)]). Although some patients showed a decrease in respiratory function measurements (5.2%), none required treatment with bronchodilators or withdrawal from the study. Only three patients had proven IFIs (and only one, a catheter-related case of disseminated fusariosis, occurred while receiving the study medication).
Recently, another example, a randomised study in the Netherlands compared the prophylaxis with liposomal amphotericin B versus placebo in neutropenic patients with a high IFI risk. A total of 271 high-risk patients with haematological disease were studied during 407 neutropenic episodes. The prophylactic regimen consisted of fluconazole combined with liposomal amphotericin B (Abelcet®) inhalation, two consecutive days per week (12.5 mg in 30 minutes, with a maximum of 12 inhalations per episode) using an adapted nebuliser delivery system. According to the intent-to-treat (ITT) analysis, 18 of 132 patients (14%) in the placebo group developed invasive aspergillosis (IPA), versus 6 of 139 patients (4%) in the ABLC group (P=0.005). According to the on-treatment analysis (OT), 13 of 97 patients (13%) in the placebo group versus 2 of 91 (2%) in the ABLC group developed IPA (P=0.007). This experience has prompted a respected editorial to regard this method as an antifungal prophylactic.
In conclusion, 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.
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 event that the working hypothesis is confirmed, 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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Drug: AMPHOTERICIN B
The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.
Other Name: Abelcet® 5 mg/ml
|Study Arm (s)||Experimental: Amphotericin B (ABELCET®)
Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
Intervention: Drug: AMPHOTERICIN B
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Enrollment ICMJE||30|
|Estimated Completion Date||January 2014|
|Primary Completion Date||August 2013 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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||3 Years to 17 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||Spain|
|NCT Number ICMJE||NCT01615809|
|Other Study ID Numbers ICMJE||FSJD-ABELNEB-2010|
|Has Data Monitoring Committee||No|
|Responsible Party||Fundació Sant Joan de Déu|
|Study Sponsor ICMJE||Fundació Sant Joan de Déu|
|Collaborators ICMJE||Ministry of Health, Spain|
|Information Provided By||Fundació Sant Joan de Déu|
|Verification Date||December 2013|
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