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

• Sponsor: Fundació Sant Joan de Déu (Other)
• Overall Status: Completed
• CT.gov ID: NCT01615809
• Collaborator: Ministry of Health, Spain (Other)
• Enrollment: 32
• Location: 1
• Arm: 1
• Duration (Months): 21
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Invasive Pulmonary Aspergillosis; Lymphoblastic Leukaemia; Myeloblastic Leukaemia; Lymphoblastic Leukemia; Myeloblastic Leukemia	Drug: AMPHOTERICIN B	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Amphotericin B (ABELCET®) 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; The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.; Other Names: Abelcet® 5 mg/ml

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Sant Joan de Déu	Esplugues de Llobregat	Barcelona	Spain	08950

Sponsors and Collaborators

• Fundació Sant Joan de Déu
• Ministry of Health, Spain

Investigators

• Principal Investigator: Jesus Estella, PhMD, Hospital Sant Joan de Deu

Study Documents (Full-Text)

None provided.

More Information

Publications

• Alexander BD, Dodds Ashley ES, Addison RM, Alspaugh JA, Chao NJ, Perfect JR. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2006 Mar;8(1):13-20.
• Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002 Jan 1;34(1):7-14. Epub 2001 Nov 26.
• Blyth CC, Palasanthiran P, O'Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007 Apr;119(4):772-84. Review.
• Bodey GP, Anaissie EJ, Elting LS, Estey E, O'Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer. 1994 Apr 15;73(8):2099-106.
• Boettcher H, Bewig B, Hirt SW, Möller F, Cremer J. Topical amphotericin B application in severe bronchial aspergillosis after lung transplantation: report of experiences in 3 cases. J Heart Lung Transplant. 2000 Dec;19(12):1224-7.
• Herbrecht R. Improving the outcome of invasive aspergillosis: new diagnostic tools and new therapeutic strategies. Ann Hematol. 2002;81 Suppl 2:S52-3.
• Herbrecht R. The changing epidemiology of fungal infections: are the lipid-forms of amphotericin B an advance? Eur J Haematol Suppl. 1996;57:12-7. Review.
• Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001 Feb 1;32(3):358-66. Epub 2001 Jan 26. Review.
• Nakagawa Y. [Prophylactic administration of fluconazole and itraconazole in febrile neutropenia associated with hematopoietic malignancy]. Jpn J Antibiot. 2006 Oct;59(5):407-9. Japanese.
• Perfect JR, Klotman ME, Gilbert CC, Crawford DD, Rosner GL, Wright KA, Peters WP. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis. 1992 May;165(5):891-7.
• Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Löwenberg B, Vulto A, Lugtenburg PJ, de Marie S. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008 May 1;46(9):1401-8. doi: 10.1086/586739.
• Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999 Mar 11;340(10):764-71.
• Walsh TJ, Gonzalez C, Lyman CA, Chanock SJ, Pizzo PA. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis. 1996;11:187-290. Review.
• Walsh TJ, Hiemenz J, Pizzo PA. Evolving risk factors for invasive fungal infections--all neutropenic patients are not the same. Clin Infect Dis. 1994 May;18(5):793-8.
• Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996 Jun;10(2):365-400. Review.

• Responsible Party: Fundació Sant Joan de Déu
• ClinicalTrials.gov Identifier: NCT01615809
• Other Study ID Numbers: FSJD-ABELNEB-2010
• First Posted: Jun 11, 2012
• Last Update Posted: Mar 29, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Fundació Sant Joan de Déu: Invasive pulmonary aspergillosis; IFI; Leukaemia; Leukemia; Pediatric; Paediatrics; Amphotericin B; Aspergillosis; Pulmonary Aspergillosis; Invasive Aspergillosis; Antifungal agents; Fungal infections; Invasive Fungal Infection
• Additional relevant MeSH terms: Aspergillosis; Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myeloid; Amphotericin B; Liposomal amphotericin B

Study Results

Participant Flow

Arm/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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). 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.
Period Title: Overall Study
STARTED	32
COMPLETED	22
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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.
Overall Participants	32
Age, Customized (participants) [Number]
>= 3 years to <=18 years	32 100%
Sex: Female, Male (Count of Participants)
Female	13 40.6%
Male	19 59.4%
Race/Ethnicity, Customized (participants) [Number]
caucasian	27 84.4%
amerindian	2 6.3%
african	1 3.1%
gypsies	2 6.3%
Region of Enrollment (center) [Number]
Spain	32

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability
Description	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

Outcome Measure Data

Analysis Population Description

pediatric patients

Arm/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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). 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.
Measure Participants	32
Number [participants]	0 0%

2. Secondary Outcome

Title	Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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). 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.
Measure Participants	32
Number [participants]	3 9.4%

3. Secondary Outcome

Title	Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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). 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.
Measure Participants	32
Number (95% Confidence Interval) [percentage of deaths]	0

Adverse Events

Arm/Group Title	Amphotericin B (ABELCET®)
Arm/Group Description	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). 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.
All Cause Mortality
	Amphotericin B (ABELCET®)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Amphotericin B (ABELCET®)
	Affected / at Risk (%)	# Events
Total	22/32 (68.8%)
Blood and lymphatic system disorders
febrile neutropenia	16/32 (50%)	26
Febrile Aplasia	3/32 (9.4%)	3
macroscopic hematuria	1/32 (3.1%)	3
General disorders
fever	8/32 (25%)	13
Metabolism and nutrition disorders
hyperglycemia	2/32 (6.3%)	3
Nervous system disorders
Methotrexate-induced neurotoxicity	3/32 (9.4%)	3
Other (Not Including Serious) Adverse Events
	Amphotericin B (ABELCET®)
	Affected / at Risk (%)	# Events
Total	32/32 (100%)
Gastrointestinal disorders
abdominal pain	29/32 (90.6%)	32
diarrhea	21/32 (65.6%)	32
General disorders
Fever	32/32 (100%)	32
paleness	28/32 (87.5%)	32
physical pain	24/32 (75%)	32

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.