Efficacy and Safety of High-dose Liposomal Amphotericin B for Disseminated Histoplasmosis in AIDS
- Conditions
- ImmunosuppressionDisseminated Histoplasma Capsulatum InfectionAIDS and InfectionsFungal Infection
- Interventions
- Drug: Single high dose of liposomal amphotericin BDrug: L-AmB standard dose
- Registration Number
- NCT05814432
- Lead Sponsor
- Federal University of Health Science of Porto Alegre
- Brief Summary
Phase III trial evaluating the safety and efficacy of a single high dose (10 mg/kg) of liposomal amphotericin B for disseminated histoplasmosis in AIDS patients, in comparison to standard therapy (3 mg/kg of liposomal amphotericin B for two weeks) (INDUCTION trial).
- Detailed Description
Histoplasmosis is a serious endemic mycosis that may disseminate in immunocompromised patients. The disease in endemic in the American continent, particularly Brazil. Patients with advanced HIV infection are susceptible to disseminated histoplasmosis, an AIDS-defining illness. According to international guidelines, induction therapy for disseminated histoplasmosis involves the use of liposomal amphotericin B for two weeks, but access to this medication is limited in several regions of the globe. A phase II trial showed promising results with the use of a single high dose of liposomal amphotericin B in this context. Here we propose a phase III study aimed to evaluate safety and efficacy of induction therapy with liposomal amphotericin B for disseminated histoplasmosis in AIDS, comparing 10 mg/kg (interventional arm) versus 3 mg/kg for two weeks (standard therapy). Induction therapy will be followed by oral itraconazole for one year for all patients.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 254
- Adult patients admitted to the centers that will be part of the study
- Infected by the HIV, regardless of the use of antiretroviral therapy
- Patients diagnosed with disseminated histoplasmosis, confirmed by classical mycological methods (microscopy, culture or histopathology) or urinary Histoplasma antigen detection
- Patients with central nervous system (CNS) infection may be included if they have an alternative diagnosis suggestive of another CNS infection
- Patients using fluconazole for oroesophageal candidiasis may be included
Exclusion criteria:
- Refusal to participate in the trial
- Previous diagnosis of histoplasmosis
- Pregnant or lactating women
- Patients with renal failure at any given time (serum creatinine > 2x or upper limit of normality (KDIGO, 2012)
- Previous severe reaction to a polyene antifungal
- Receipt of more than one dose of a polyene antifungal in the last 48 h
- Suspected histoplasmosis involving the central nervous system
- Patients who, in the judgment of the attending physician, have the prospect of death within the next 48 hours after selection, will also be excluded
- Patients with suspected histoplasmosis involving the central nervous system (CNS), as this condition requires high doses of amphotericin B
- Patients with the prospect of death in the next 48 hours after selection
- Patients with a concomitant diagnosis of cryptococcus will be excluded, as will patients with leishmaniasis in treatment or in secondary prophylaxis with amphotericin
- Patients without the capacity to administer enteral medication-at the discretion of the principal investigator of each center-considering that these patients will not be able to use itraconazole orally or through a feeding tube
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Single high dose arm Single high dose of liposomal amphotericin B Single high dose of liposomal amphotericin B (10 mg/kg) Standard dose arm L-AmB standard dose Standard treatment with 3 mg/kg of liposomal amphotericin B daily for 2 weeks
- Primary Outcome Measures
Name Time Method Overall survival rate 14 days Overall mortality (from any cause) will be determined on day 14 of the study
- Secondary Outcome Measures
Name Time Method Desirability of Outcome Ranking (DOOR) score Evaluated on week 10 DOOR categorized as follows:
(i) Death within the first 10 weeks of randomization or lost to follow up within 2 weeks
(ii) SAE in the first 10 weeks
(iii) Grade 4 laboratory abnormality in the first 2 weeks (electrolytes, anemia/leukopenia or renal dysfunction)
(iv) Grade 3 laboratory abnormality in the first 2 weeks (electrolytes, anemia/leukopenia or renal dysfunction) or lost to follow up from 2-10 weeks
(v) alive at week 10Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] Evaluated on day 14 Safety outcomes will be evaluated using a clinical record, with continuous monitoring of the appearance of any suspected adverse event, since the first administration of the drug. The Frequency of grade 3 or 4 toxicities will be determined according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.
Clinical response rate Evaluated on day 14 A successful clinical response to induction therapy will be defined as absence of fever for at least 72 hours and no increase in the severity of clinical signs, symptoms, or laboratory abnormalities attributable to histoplasmosis.
Rate of reduction in the concentration of Histoplasma urinary antigen Evaluated on day 14 The effect of at least a 50% decrease in Histoplasma urinary antigen concentrations over the first two weeks of therapy will be determined.
Fungal load reduction rate in blood samples Evaluated on day 14 The result of qPCR on blood sample will be analyzed to measure the reduction of load of histoplasmosis on DNA on day 14, in comparison to baseline.
Number of patients requiring additional antifungal treatment 10-week The need for an additional antifungal course of L-AmB during the 10-week follow-up (considered as treatment failures), as well as days of hospitalization.
Overall survival rate Evaluated on week 10 Overall mortality (from any cause) will be determined on week 10 of the study
Trial Locations
- Locations (5)
Hospital de Doenças Tropicais
🇧🇷Goiania, Goias, Brazil
Hospital Giselda Trigueiro
🇧🇷Natal, Rio Grande do Norte, Brazil
Federal University of Health Sciences of Porto Alegre
🇧🇷Porto Alegre, Rio Grande do Sul, Brazil
Hospital de Clinicas de Porto Alegre
🇧🇷Porto Alegre, Rio Grande do Sul, Brazil
Hospital Geral de Roraima
🇧🇷Boa Vista, Roraima, Brazil