Efficacy and Safety of High-dose L-AmB for Disseminated Histoplasmosis in AIDS

Study Overview
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Brief Summary
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Histoplasmosis is a systemic mycosis endemic in the Americas and Brazil. HIV-infected patients are susceptible to disseminated histoplasmosis (HD), AIDS-defining illness. The classic diagnosis requires a fungal culture that takes 4-6 weeks to grow. Brazilian patients are diagnosed by culture or by histopathology and American patients have their diagnosis in 1-2 days, by Histoplasma antigen detection in urine. Amphotericin B treatment Liposomal (L-AmB) is recommended by the American Society for Infectious Diseases and WHO, while the Brazilian AIDS Program does not fund the use of L-AmB, delegating responsibility to the states. As a result, patients with AIDS+HD do not have access to new diagnostic tests or L-AmB, receiving late treatment with AmB-d, which results in increased mortality >45%. The single high dose liposomal amphotericin B treatment study, aims to improve the availability of access to medication, something that has already been demonstrated successfully by our group in a phase II study. This proposal seeks to determine the efficacy and safety of two L-AmB regimens as induction therapy for HD in AIDS patients: 10 mg/kg single dose versus 3 mg/kg for two weeks.

Official Title
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Efficacy and Safety of High-dose Liposomal Amphotericin B (10 mg/kg) for Disseminated Histoplasmosis in AIDS: a Randomized Phase III Trial

Conditions
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Disseminated Histoplasma Capsulatum Infection, AIDS and Infections, Immunosuppression, Fungal Infection

Intervention / Treatment
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* Drug: Liposomal Amphotericin B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients admitted to the centers that will be part of the study. Infected by HIV in AIDS and diagnosed with DH, through: (i) positive Histoplasma antigen in the urine (monoclonal antibody test IMMY® Clarus); (ii) confirmation by classical mycological methods; or (iii) positive qualitative in-house Histoplasma polymerase chain reaction (PCR) test (according to the availability of the centers). Patients regardless of the use of antiretroviral therapy (ART). Exclusion Criteria: Patients with a previous diagnosis of histoplasmosis. Pregnant or lactating women. Patients with renal impairment (serum creatinine and BUN >1.5x the upper limit of normal) and patients with a previous severe reaction to a polyene antifungal.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm High Dose<br>High dose of medication on the first day (10mg/kg) | Drug: Liposomal Amphotericin B<br>* Single high dose (10mg/kg) Standard treatment on 14 days (3mg/kg)<br>|
| Active Comparator: Arm Standard Dose<br>Standard treatment on the next two weeks (3mg/kg) | Drug: Liposomal Amphotericin B<br>* Single high dose (10mg/kg) Standard treatment on 14 days (3mg/kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | A clinical answer successful induction therapy will be set according to the maximum temperature (ºC) daily 72 hours and no increase in the severity of clinical signs, symptoms or laboratory abnormalities attributable to histoplasmosis (e.g., weight instabilities (kg), blood pressure (mmHg) and blood oxygen level (mg/L)).The primary outcome will be determined on the 14th day after the baseline state and will be measured through a questionnaire with clinical information from patient follow-up with this clinical information. | Between the basal day and 14th day | 
| Emergence monitoring of any suspected adverse event | The safety outcome will be evaluated by means of a clinical record, with continuous monitoring of the emergence of any suspected adverse event, since the first administration of the drug. | Between the basal day and 14th day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Overall mortality (from any cause) and the mortality due to histoplasmosis (directly related and attributed by the investigator) will be determined on day 14 of the study. | 14 days | 
| Liver and kidney dysfunction | The mean percentage of changes in liver function and kidney (U/L) at 14 days will be compared with baseline values. The frequency of toxicity related to L-AmB infusion will be recorded. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Disseminated Histoplasma, AIDS, L-AmB, Fungal infection