Invasive Pulmonary Aspergillosis, Lymphoblastic Leukaemia, Lymphoblastic Leukemia, Myeloblastic Leukaemia, Myeloblastic Leukemia
Conditions
Keywords
Invasive pulmonary aspergillosis, IFI, Leukaemia, Leukemia, Pediatric, Paediatrics, Amphotericin B, Aspergillosis, Pulmonary Aspergillosis, Invasive Aspergillosis, Antifungal agents, Fungal infections, Invasive Fungal Infection
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.
Interventions
DRUGAMPHOTERICIN B
The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.
Sponsors
Ministry of Health, Spain
Fundació Sant Joan de Déu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability | at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis | at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks | 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. |
| Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®. | at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks | Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amphotericin B (ABELCET®) Patients fulfilling inclusion criteria and those giving the general informed consent for the study initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
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 was 10 ml (50 mg) twice a week for the first week, and then from the second week onwards was reduced to 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count demonstrated to be greater than or equal to 1500 cells/mm3. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Amphotericin B (ABELCET®) |
|---|---|
| Age, Customized >= 3 years to <=18 years | 32 participants |
| Race/Ethnicity, Customized african | 1 participants |
| Race/Ethnicity, Customized amerindian | 2 participants |
| Race/Ethnicity, Customized caucasian | 27 participants |
| Race/Ethnicity, Customized gypsies | 2 participants |
| Region of Enrollment Spain | 32 center |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 32 / 32 |
| serious Total, serious adverse events | 22 / 32 |
Outcome results
Primary
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).
Time frame: at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks
Population: pediatric patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amphotericin B (ABELCET®) | Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability | 0 participants |
Secondary
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.
Time frame: at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks
Population: At baseline, none of the 32 pediatric patients with acute leukemia included in the clinical trial had API. During the trial period there were 3 patients who developed API
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amphotericin B (ABELCET®) | Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis | 3 participants |
Secondary
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.
Time frame: at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amphotericin B (ABELCET®) | Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®. | 0 percentage of deaths |