Itraconazole Versus Amphotericin B for the treatment of Penicilliosis (IVAP)

INTERVENTION:

Current interventions as of 15/02/2012: This study is a randomized, open‐label, comparative, multi‐center trial designed to assess the efficacy and safety of itraconazole versus amphotericin B for the acute‐phase treatment of penicilliosis in patients infected with HIV in Viet Nam. Patients will be randomized at 1:1 ration to the following treatment arms: Group 1: intravenous amphotericin B 0.7 mg/kg/day for 2 weeks Group 2: oral itraconazole 600 mg/day x first 3 days + 400 mg/day x 11 days After the 2‐week acute phase therapy, all patients will continue on to the maintain‐phase therapy with oral itraconazole 400 mg/day for 10 weeks, followed by the suppressive phase therapy with itraconazole 200 mg/day until CD4 count rises above 100 for 6 months on antiretroviral therapy for HIV. Randomization will be stratified by study site. Previous interventions This study is a randomized, open‐label, comparative, multi‐center trial designed to assess the efficacy and safety of itraconazole versus amphotericin B for the acute‐phase treatment of penicilliosis in patients infected with HIV in Viet Nam. Patients will be randomized at 1:1 ration to the following treatment arms: Group 1: intravenous amphotericin B 0.6 mg/kg/day for 2 weeks Group 2: oral itraconazole 400 mg/day for 2 weeks After the 2‐week acute phase therapy, all patients will continue on to the maintain‐phase therapy with oral itraconazole 400 mg/day for 10 weeks, followed by the suppressive phase therapy with itraconazole 200 mg/day until CD4 count rises above 100 for 6 months on antiretroviral therapy for HIV. Randomization will be stratified for the following variables: 1. Study site 2. Presence of fungemia

CONDITION:

Penicillium marneffei ; Infections and Infestations ; Human immunodeficiency virus (HIV) disease resulting in infectious and parasitic diseases

PRIMARY OUTCOME:

Current primary outcome as of 15/02/2012:; Absolute risk of death during the first 2 weeks after randomization; ; Previous primary outcome:; Mortality at 2 weeks of treatment (most deaths from penicilliosis occur in the acute phase of the disease and are reasonably assumed to have occurred by week 2 of presentation)

SECONDARY OUTCOME:

Current secondary outcomes as of 25/07/2013:; 1.Clinical endpoints ; 1.1 Overall survival until week 24 ; 1.2 Time to treatment success (defined by absence of fungal growth in follow up culture, temperature <38ºC for 3 days, and complete resolution of lesions or lesions in the final stage of healing as judged by treating clinicians) ; 1.3 Relapse‐free survival until week 24 of therapy (i.e., time from treatment success to the first treatment relapse or death). (Relapse is defined as recurrence of culture‐confirmed penicilliosis after achieving treatment success at week 12) ; 1.4 Deaths from penicilliosis until week 24 (causes of death will be determined by investigators) ; 1.5 Time to change of therapy from assigned study therapy ; 1.6 Total number of patients with Grade 3 and Grade 4 AEs and SAEs, and the cumulative incidence of Grade 3 and Grade 4 AEs and SAEs, associated with cessation of randomly assigned therapy between treatment arms ; 1.7 Antifungal medication adherence ; 1.8 Incidence of Immune Reconstitution Diseases ; 2. Microbiological endpoints ; 2.1 Time to blood culture sterilization ; 2.2 Rate of early fungicidal activity as determined by serial blood samplings during therapy and measured by the decrease in log colony forming units per mL of blood (CFUs/mL) ; 2.3 Frequency and patterns of itraconazole and amphotericin B resistance emergence ; 3. Pharmacological endpoints ; 3.1 Antifungal concentration time curves ; 3.2 Maximum antifungal concentrations/MIC, area under the curve (AUC) of antifungals/MIC over time ; ; Previous secondary outcomes (15/02/2012 to 25/07/2013):; 1.Clinical endpoints; 1.1 Overall survival until week 24; 1.2 Time to treatment success (defined by absence of fungal growth in follow up culture, temperature <38ºC for 3 days, and complete resolution of lesions or lesions in the final stage of healing as judged by treating clinicians) ; 1.3 Relapse‐free survival until week 24 of therapy (i.e., time from treatment success to the first treatment relapse or death). (Relapse is defined as recurrence of culture‐confirmed penicilliosis after achieving treatment success at week 12) ; 1.4 Deaths from penicilliosis until week 24 (causes of death will be determined by investigators); 1.5 Time to change of therapy from assigned study therapy; 1.6 Total number of patients with Grade 3 and Grade 4 AEs and SAEs, and the cumulative incidence of Grade 3 and Grade 4 AEs and SAEs, associated with cessation of randomly assigned therapy between treatment arms; 1.7 Antifungal medication adherence; 1.8 Incidence of Immune Reconstitution Diseases; 2. Microbiological endpoints; 2.1 Time to blood culture sterilization; 2.2 Rate of early fungicidal activity as determined by serial blood samplings during therapy and measured by the decrease in log colony forming units per mL of blood (CFUs/mL); 2.3 Frequency and patterns of itraconazole and amphotericin B resistance emergence ; 3. Pharmacological endpoints; 3.1 Antifungal concentration time curves ; 3.2 Maximum antifungal concentrations/MIC, area under the curve (AUC) of antifungals/MIC over time; 4. Serological endpoints; 4.1 Time to P. marneffei urinary antigen clearance; 4.2 Rate of decrease in P. marneffei urinary antigen titers; ; Original secondary outcomes (until 15/02/2012):; 1. Clinical endpoints:; 1.1. Overall survival until week 24; 1.2. Time to treatment success (defined by absence of fungal growth in follow up culture, temperature <38ºC for 3 days, and complete resolution of lesions or lesions in the final stage of healing as judged by treating clinicians) ; 1.3. Relapse‐free survival until week 24 of therapy (i.e. time from treatment success to the first treatment relapse or death). (Relapse is defined as recurrence of culture‐confirmed penicilliosis after achieving treatment success at week 12) ; 1.4. Time to change in randomly assigned therapy; 1.5. Total number of patients with Grade 3 and Grade 4 AEs and SAEs, and the cumulative incidence of Grade 3 and Grade 4 AEs and SAEs, associated with cessation of randomly assigned therapy between treatment arms; 1.6. Antifungal medication adherence; 2. Microbiological endpoints:; 2.1. Time to blood culture sterilization; 2.2. Rate of early fungicidal activity as determined by serial blood samplings during therapy and measured by the decrease in log colony forming units per mL of blood (CFUs/mL); 2.3. Frequency and patterns of itraconazole and amphotericin B resistance emergence by E‐test; 3. Pharmacological endpoints:; 3.1. Antifungal concentration time curves in central (plasma) and PBM intracellular compartments; 3.2. Maximum antifungal concentrations/MIC, area under the curve (AUC) of antifungals/MIC over time; 4. Serological endpoints:; 4.1. Time to P. marneffei urinary antigen clearance; 4.2. Rate of decrease in P. marneffei urinary antigen titers

INCLUSION CRITERIA:

Current inclusion criteria as of 15/02/2012 1. HIV positive AND 2. Age =18 years AND 3. Syndrome consistent with penicilliosis (primary or relapse) PLUS culture‐confirmed diagnosis of penicilliosis (from blood, skin lesion scrapping, lymph node or bone marrow biopsy). Previous inclusion criteria 1. HIV positive 2. Age = 15 years 3. Male and female participants 4. Syndrome consistent with penicilliosis (fever, malaise, hepatosplenomegaly, lymphadenopathy, typical skin lesions) plus culture confirmed diagnosis of penicilliosis (from blood, skin lesion scrapping/biopsy, lymph node or bone marrow biopsy)