Liposomal Amphotericin B (Ambisome) Versus Oral Voriconazole for the Prevention of Invasive Fungal Infections

Study Overview
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Brief Summary
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The goal of this clinical research study is to compare the effectiveness of liposomal amphotericin B given three times per week , versus liposomal amphotericin B given once per week, versus oral voriconazole in the prevention of fungal infections in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes MDS who are receiving chemotherapy. The safety of these treatments will also be studied and compared.

Detailed Description
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Ambisome and voriconazole are drugs that have been used to fight fungal infections, which typically occur during chemotherapy as a result of lowered immune system functioning. Ambisome works by binding to the sterol component of the fungal cell membrane. This causes holes to appear in the membrane, which leads to death of the fungal cell. Voriconazole inhibits an essential step of the biosynthesis of an important component of the fungal cell wall (ergosterol). This causes the impairment of the fungal cell wall. Before you can start treatment on this study, you will have screening tests. These tests will help the doctor decide if you are eligible to take part in this study. You will be asked questions about your medical history. You will have a complete physical exam and a chest x-ray. You will have computed tomography (CT) scans of the chest. You will also have about 1 teaspoon of blood drawn for routine tests. Test results from the pregnancy test that you will have before your leukemia treatment will be looked at for this study. You will not have a pregnancy test performed for this study. If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to one of 3 treatment groups (Group 1, Group 2, or Group 3). Participants in Groups 1 and 2 will receive treatment with ambisome. Participants in Group 3 will receive treatment with voriconazole. Participants in all 3 groups will begin treatment 24 hours after the last dose of chemotherapy. If you are assigned to Group 1, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per day, 3 times each week. If you are assigned to Group 2, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per week. If you are assigned to Group 3, you will take 2 pills by mouth (1 hour after breakfast) and 2 pills by mouth (1 hour after dinner) for 1 day, which amounts to 4 pills in total on Day 1. You will then take 1 pill by mouth (1 hour after breakfast) and 1 pill by mouth (1 hour after dinner) everyday for the remainder of this study, which amounts to 2 pills in total each day. You will have about 1 teaspoon of blood drawn for routine tests 2 times each week. You will also receive treatment with standard of care medications. These medications (which will be specified by your doctor) will be used to help decrease the risk of developing bacterial infections and viral infections. If you develop a fever during treatment on this study, you will have a chest x-ray and a CT scan of the chest within 3 days after the fever started. You may remain on this study for up to 35 days (if you are receiving chemotherapy for the first time) and up to 42 days (if you have had prior chemotherapy). Your participation may end on this study if your study doctor thinks it is necessary, if other antifungal therapy is required, or if you develop any intolerable side effects.

Official Title
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Open, Randomized Comparative Trial of Two Different Schedules of Liposomal Amphotericin B Versus Oral Voriconazole for the Prevention of Invasive Fungal Infections

Conditions
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Voriconazole
* Drug: Liposomal amphotericin B
* Drug: Liposomal amphotericin B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AML or high risk MDS undergoing induction chemotherapy or first salvage chemotherapy. Age >/=18 years. Patients must sign an informed consent. Exclusion Criteria: Patients with history of anaphylaxis attributed to azole or amphotericin B compounds. Patients with clinical or other evidence that indicates that they have proven or probable invasive fungal infection prior to enrollment. Patients with total bilirubin levels > 3 times the upper normal limits (i.e. > 3.0 mg/dl); or serum glutamic pyruvic transaminase (SGPT)> 5 times upper limit normal. Patients with serum creatinine > 2.0 mg/dl. Patients receiving any medication that is contraindicated with the use of voriconazole. Patients who have participated in this study during induction chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liposomal amphotericin B: 3 mg/kg<br>3 mg/kg intravenously (IV) three times per week | Drug: Liposomal amphotericin B<br>* 3 mg/kg intravenously three times per week over 2 hours +/- 15 minutes<br>* Other names: Ambisome;|
| Experimental: Liposomal amphotericin B: 9 mg/kg<br>9 mg/kg IV once per week | Drug: Liposomal amphotericin B<br>* 9 mg/kg intravenously once per week over 2 hours +/- 15 minutes<br>* Other names: Ambisome;|
| Experimental: Voriconazole: 400 mg<br>400 mg oral twice daily day 1 followed by 200 mg twice daily | Drug: Voriconazole<br>* 400 mg by mouth twice daily on day 1, followed by 200 mg by mouth twice daily<br>* Other names: Vfend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Invasive Fungal Infection | Endpoint was whether participant had an invasive fungal infection or not, a potentially fatal complication with leukemia patients. Efficacy defined as absence of proven and probable fungal infection. Probable fungal infection is: 1) Positive radiographic findings consistent with fungal infections documented on CT imaging: Lower respiratory tract infection: halo sign, air crescent-sign, or cavity within areas of consolidation; Sinus: erosion of sinus walls or extension of infection to neighboring structures, extensive skull base destruction; and/or 2) Two positive galactomannan index test. | 35 days from the start of therapy for induction participants and 42 days for salvage participants. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Voriconazole, Vfend, Liposomal amphotericin B, Ambisome, Acute Myelogenous Leukemia, Myelodysplastic Syndrome, AML, MDS