Infections

All Conditions

Neoplasms

Blood and Lymph Conditions

Symptoms and General Pathology

Rare Diseases

Mycoses

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Communicable Diseases

Invasive Fungal Infections

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neutropenia

Neoplasms by Histologic Type

Hematologic Diseases

Agranulocytosis

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Bacterial Infections

Bacterial Infections and Mycoses

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Granulocytopenia

Acute Graft Versus Host Disease

Anti-Infective Agents

All Drugs and Chemicals

Clotrimazole

Miconazole

Antifungal Agents

Posaconazole

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

POS 200 mg three times a day (TID) on Days 1-8 followed by continued randomized dosing regimen of POS 200 mg TID on Days 9-15, administered with food or oral nutritional supplements.

POS 200 mg TID on Days 1-8 followed by randomized dosing regimen of POS 400 mg twice a day (BID) on Days 9-15, administered with food or oral nutritional supplements.

POS 200 mg TID on Days 1-8 followed by randomized dosing regimen of POS 400 mg TID on Days 9-15, administered with food or oral nutritional supplements.

Posaconazole will be used for prophylaxis

The purpose of this study is: to explore the potential for different dosing strategies of posaconazole oral suspension (POS) to increase plasma levels and to profile the pharmacokinetics of these dosing strategies in patients with compromised gastrointestinal function and at high risk for Invasive Fungal Infection.

Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)

A Phase 4 Study of the Pharmacokinetics of Oral Posaconazole (SCH 56592) Among Patients With Compromised Gastrointestinal Function and at High Risk for Invasive Fungal Infection

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php

Individual mean concentrations were calculated as the average of observed concentrations at 0 hour (before the morning dose) and 5 hours after the morning dose.

Individual mean concentrations calculated as the average of observed concentrations at 0 hour (before the morning dose) and 5 hours after the morning dose.

Merck Sharp & Dohme LLC

POS 200 mg TID on Days 1-8, administered with food or oral nutritional supplements.

POS 200 mg TID on Days 1-8

POS 200 mg TID on Days 9-15, administered with food or oral nutritional supplements.

POS 200 mg TID on Days 9-15

POS 400 mg on Days 9-15, administered with food or oral nutritional supplements.

POS 400 mg BID on Days 9-15

POS 400 mg TID on Days 9-15, administered with food or oral nutritional supplements.

POS 400 mg TID on Days 9-15

POS 200 mg TID on Days 1-8, administered with food or oral nutritional supplements (participants who discontinued anytime before randomization on Day 8).

Not Randomized

POS 200 mg TID on Days 1-8 Followed by POS 200 mg TID on Days 9-15, administered with food or oral nutritional supplements (participants who received POS 200 mg TID on Days 1-8 and were then randomized to continue with POS 200 mg TID on Days 9-15).

POS 200 mg TID Days 1-8 Followed by POS 200 mg TID Days 9-15

POS 200 mg TID on Days 1-8 followed by POS 400 mg BID on Days 9-15, administered with food or oral nutritional supplements (participants who received POS 200 mg TID on Days 1-8 and were then randomized to POS 400 mg BID on Days 9-15).

POS 200 mg TID Days 1-8 Followed by POS 400 mg BID Days 9-15

POS 200 mg TID on Days 1-8 followed by POS 400 mg TID on Days 9-15, administered with food or oral nutritional supplements (participants who received POS 200 mg TID on Days 1-8 and were then randomized to POS 400 mg TID on Days 9-15).

POS 200 mg TID Days 1-8 Followed by POS 400 mg TID Days 9-15

Total

Age, Categorical

Sex: Female, Male

Senior Vice President, Global Clinical Development

Day 2

Day 3

Day 8

POS 200 mg TID on Days 1-8, administered with food or oral nutritional supplements (participants who received POS 200 mg TID on Days 1-8 and were then randomized to one of the three dosing regimens for Days 9-15).

POS 200 mg TID Days 1-8

Analysis of the primary outcome was done on the Balanced Data Set, defined as all participants with no missing pharmacokinetic data for Days 3, 8, and 15 (n=49). From Days 1 to 8, these 49 participants received 200 mg TID. From Days 9 to 15, these 49 participants were randomized to either 200 mg TID (n=19), 400 mg BID (n=14), or 400 mg TID (n=16).

Mean POS Plasma Concentrations on Days 2, 3, and 8.

Day 15

Mean POS Plasma Concentrations on Days 8 and 15 Stratified by Randomized Dosing Regimen

Day 3 <250 ng/mL and Day 8 <500 ng/mL

Day 3 <250 ng/mL and Day 8 ≥500 ng/mL

Total Day 3 <250 ng/mL

Day 3 ≥250 ng/mL and Day 8 <500 ng/mL

Day 3 ≥250 ng/mL and Day 8 ≥500 ng/mL

Total Day 3 ≥250 ng/mL

Participants With a Mean POS Plasma Concentration ≥/<250 ng/mL on Day 3 and ≥/<500 ng/mL on Day 8

Day 3 <350 ng/mL and Day 8 <700 ng/mL

Day 3 <350 ng/mL and Day 8 ≥700 ng/mL

Total Day 3 <350 ng/mL

Day 3 ≥350 ng/mL and Day 8 <700 ng/mL

Day 3 ≥350 ng/mL and Day 8 ≥700 ng/mL

Total Day 3 ≥350 ng/mL

Participants With a Mean POS Plasma Concentration ≥/<350 ng/mL on Day 3 and ≥/<700 ng/mL on Day 8

Day 8 <250 ng/mL and Day 15 <500 ng/mL

Day 8 <250 ng/mL and Day 15 ≥500 ng/mL

Total Day 8 <250 ng/mL

Day 8 ≥250 ng/mL and Day 15 <500 ng/mL

Day 8 ≥250 ng/mL and Day 15 ≥500 ng/mL

Total Day 8 ≥250 ng/mL

Participants With a Mean POS Plasma Concentration ≥/<250 ng/mL on Day 8 and ≥/<500 ng/mL on Day 15

Day 8 <350 ng/mL and Day 15 <700 ng/mL

Day 8 <350 ng/mL and Day 15 ≥700 ng/mL

Total Day 8 <350 ng/mL

Day 8 ≥350 ng/mL and Day 15 <700 ng/mL

Day 8 ≥350 ng/mL and Day 15 ≥700 ng/mL

Total Day 8 ≥350 ng/mL

Participants With a Mean POS Plasma Concentration ≥/<350 ng/mL on Day 8 and ≥/<700 ng/mL on Day 15

Posaconazole oral suspension (POS) 200 mg Three Times a Day (TID) on Days 1-8, administered with food or oral nutritional supplements (participants who discontinued anytime before randomization on Day 8)

POS 200 mg TID on Days 1-8 followed by POS 400 mg Twice a Day (BID) on Days 9-15, administered with food or oral nutritional supplements (participants who received POS 200 mg TID on Days 1-8 and were then randomized to POS 400 mg BID on Days 9-15).

Overall Study

Immune System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Aspergillosis

Invasive Pulmonary Aspergillosis

Pulmonary Aspergillosis

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lung Diseases

Lung Diseases, Fungal

Respiratory Tract Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Amphotericin B

Liposomal amphotericin B

Amebicides

Anti-Bacterial Agents

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.

The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.

AMPHOTERICIN B

Jesus Estella, PhMD

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.

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.

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

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

Anonymized individual data of participants will be shared with Authorities at the end of the Clinical Development Plan by the CTD (Common Technical Document). Results will be published in a scientific publication.

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).

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.

Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy.

Ministry of Health, Spain

Fundació Sant Joan de Déu

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.

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.

>= 3 years to <=18 years

Age, Customized

caucasian

amerindian

african

gypsies

patients ethnicity percentage : caucasian (84.4%), Amerindian (6.3%), African (3.1%) and gypsies (6.3%).

Race/Ethnicity, Customized

Spain

Region of Enrollment

Rosa Maria morales Palau

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

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

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)	NCT00686543	Fungal Infectio... Acute Myelogeno... Neutropenia	Posaconazole	18 Years -	Merck Sharp & Dohme LLC
Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia	NCT01615809	Invasive Pulmon... Lymphoblastic L... Myeloblastic Le... Lymphoblastic L... Myeloblastic Le...	AMPHOTERICIN B	3 Years - 17 Years	Fundació Sant Joan de Déu
Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)	NCT00686543	Fungal Infectio... Acute Myelogeno... Neutropenia	Posaconazole	18 Years -	Merck Sharp & Dohme LLC

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