Randomized Trial of Liposomal Amphotericin B for Histoplasmosis in AIDS Patients

Overview

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.

Full Title of Study: “Open Label Phase-II Randomized Trial of Three Liposomal Amphotericin B Regimens as Induction Therapy for Disseminated Histoplasmosis in AIDS Patients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 31, 2021

Detailed Description

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.

Interventions

  • Drug: single dose of L-AmB
    • (i) single IV dose of 10 mg/kg of L-AmB on day 1;
  • Drug: 2 doses of L-AmB
    • (ii) 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 weeks of L-AmB
    • (iii) IV dose of 3 mg/kg of L-AmB for 2 weeks.

Arms, Groups and Cohorts

  • Experimental: single dose of L-AmB
    • single IV dose of 10 mg/kg of L-AmB on day 1;
  • Experimental: 2 doses of L-AmB
    • IV dose of 10 mg/kg of L-AmB on day 1, followed by 5 mg/kg of L-AmB on day 3;
  • Active Comparator: 2 weeks of L-AmB
    • IV dose of 3 mg/kg of L-AmB for 2 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Clinical response
    • Time Frame: day 14
    • Maximum daily temperature lower than 37.8 °C
  • Weight stability
    • Time Frame: day 14
    • This parameter will be measurement by a questionnaire, based on information about the patient weight in kilograms (Kg)
  • Blood Pressure
    • Time Frame: day 14
    • Analysis if any patient presented hypotension (systolic blood pressure ˂ 90 mm Hg)
  • Blood oxygen level
    • Time Frame: day 14
    • 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

Secondary Measures

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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Alessandro Pasqualotto
  • Collaborator
    • Hospital de Clinicas de Porto Alegre
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Alessandro Pasqualotto, Principal Investigator – Federal University of Health Science of Porto Alegre
  • Overall Official(s)
    • Daiane Dalla Lana, PhD, Study Chair, Federal University of Health Science of Porto Alegre

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