Randomized Trial of Liposomal Amphotericin B for Histoplasmosis in AIDS Patients

Study Overview
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Brief Summary
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Disseminated histoplasmosis (DH) is one of the major AIDS-defining infections responsible for high mortality rates in HIV-infected patients. Liposomal amphotericin B (L-AmB) is considered the therapy of choice for AIDS-associated histoplasmosis.However, many patients in Latin America are still treated with high doses of deoxycholate amphotericin B (d-AmB) for long periods. These regimens are associated with toxicity and thus reduced efficacy. Therefore, a better treatment strategy is necessary to improve the activity of this amphotericin B treatment. Treatment with a high dose of L-AmB for short periods (rather than standard doses for longer periods) is a promising approach considering that the antifungal effect of amphotericin B depends on peak concentrations. This randomized open-label Phase II study aims to determinate and to compare the activity and safety of three L-AmB regimens, as induction therapy for DH in AIDS patients.

Detailed Description
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This is a prospective randomized non-comparative multicenter open label trial of induction therapy with LAmB for DH in AIDS patients, followed by oral therapy with itraconazole. The sample size planned is 99 patients of both sexes, older than 18 years (33 patients per study arm), infected with HIV and with confirmed diagnosis for DH. This sample size considers 10% of dropout. The study will be conducted in accordance with the Helsinki Declaration, as well as the Standards national and international Guidelines for Good Clinical Practices. Eight research centres in Brazil will competitively recruit patients: Santa Casa de Misericórdia de Porto Alegre (Porto Alegre; Dr Alessandro C. Pasqualotto), Hospital de Clínicas de Porto Alegre (Porto Alegre; Dr Diego R. Falci), Hospital Nossa Senhora da Conceição (Porto Alegre; Dr Marineide Melo), Hospital de Doenças Tropicais (Goiânia; Dr Cassia S. de Miranda Godoy), Hospital São José de Doenças Infecciosas (Fortaleza; Dr Terezinha M. J. Silva Leitão), and Hospital Giselda Trigueiro (Natal, Dr Monica B. Bay), Hospital Universitário Osvaldo Cruz (Recife, Dr. Filipe Prohaska Batista) e Instituto de Infectologia Emília Ribas (São Paulo, Dr. José Ernesto Vidal Bermudez). AIDS patients with DH will be randomized to one of three study arms: (i) single IV dose of 10 mg/kg of L-AmB; (ii) single IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3; (iii) IV dose of 3 mg/kg of L-AmB for 2 weeks. Induction therapy will be followed in all patients by oral therapy with itraconazole capsules at 400 mg/daily for a year, azole drug which is already therapy of choice for consolidation of histoplasmosis, according to national and international Guidelines.

Official Title
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Open Label Phase-II Randomized Trial of Three Liposomal Amphotericin B Regimens as Induction Therapy for Disseminated Histoplasmosis in AIDS Patients

Conditions
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Histoplasmosis, AIDS

Intervention / Treatment
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* Drug: single dose of L-AmB
* Drug: 2 doses of L-AmB
* Drug: 2 weeks of L-AmB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (> 18 years) HIV-infected hospitalized patients diagnosed with HD by the means of (i) urine Histoplasma positive antigen (IMMY® monoclonal antibody test); (ii) confirmation by classical mycological methods (microscopy, culture or histopathology); or (iii) Histoplasma positive qualitative polymerase chain reaction (PCR) in bronchoalveolar lavage samples, bone marrow aspirates or tissue samples. Patients will be included despite of the use of antiretroviral therapy (ART). Understanding and signed the Informed Consent Form. Exclusion Criteria: Patients with previous diagnosis of histoplasmosis. Pregnant or lactating women. Patients with renal insufficiency (serum creatinine and urea > 1.5x the upper limit of normal). Abnormal aminotransferases (up to > 3x the upper limit of normal) and patients with a severe prior reaction to polyene antifungal. Patients who have received more than one dose of a polyene antifungal in the last 48 hours. Patients who refuse to participate in the study. Patients diagnosed with histoplasmosis that affect the central nervous system. Patients who, at the trial of the attending physician, are expected to die within 48 hours. Patients diagnosed with tuberculosis. Patients with any disease or condition that, in the opinion of the investigator, may interfere with the assessments or participation in the study. Patients receiving drugs that cause significant (relative or absolute) drug interaction with Itraconazole.

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 |
| --- | --- |
| Experimental: single dose of L-AmB<br>single IV dose of 10 mg/kg of L-AmB on day 1; | Drug: single dose of L-AmB<br>* (i) single IV dose of 10 mg/kg of L-AmB on day 1;<br>* Other names: Intervention 1;|
| Experimental: 2 doses of L-AmB<br>IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3; | Drug: 2 doses of L-AmB<br>* (ii) IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3;<br>* Other names: Intervention 2;|
| Active Comparator: 2 weeks of L-AmB<br>IV dose of 3 mg/kg of L-AmB for 2 weeks. | Drug: 2 weeks of L-AmB<br>* (iii) IV dose of 3 mg/kg of L-AmB for 2 weeks.<br>* Other names: Intervention 3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Maximum daily temperature lower than 37.8 °C | day 14 | 
| Weight stability | This parameter will be measurement by a questionnaire, based on information about the patient weight in kilograms (Kg) | day 14 | 
| Blood Pressure | Analysis if any patient presented hypotension (systolic blood pressure ˂ 90 mm Hg) | day 14 | 
| Blood oxygen level | Normal arterial oxygen is approximately 75 to 100 millimeters of mercury (mm Hg). Values under 60 mm Hg usually indicate the need for supplemental oxygen | day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall mortality | Mortality rates attributed to the cause of death that is not directly and only related to histoplasmosis | day 14 | 
| Mortality due to histoplasmosis | Mortality rates attributed by the study investigator that are directly related to histoplasmosis | day 14 | 
| Renal function abnormalities | Microalbuminuria > 30 mg/24 h | day 14 | 
| Liver function abnormalities | Liver function abnormalities were serum levels of alanine and aspartate aminotransferase > 2.5 times normal or bilirubin levels > 2 times normal | day 14 | 
| Histoplasma urinary antigen concentrations | Decrease of at least 50% in Histoplasma urinary antigen concentrations | day 7, 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Histoplasmosis, AIDS, Liposomal amphotericin B, High dose therapy