Randomized Trial of Liposomal Amphotericin B for Histoplasmosis in AIDS Patients

• ClinicalTrials.gov Identifier: NCT04059770
• Recruitment Status: Completed
• First Posted: August 16, 2019
• Last Update Posted: March 21, 2023
• Sponsor: Alessandro Pasqualotto
• Collaborators: Hospital de Clinicas de Porto Alegre; Hospital Nossa Senhora da Conceicao; Irmandade Santa Casa de Misericórdia de Porto Alegre
• Information provided by (Responsible Party): Alessandro Pasqualotto, Federal University of Health Science of Porto Alegre

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Histoplasmosis; AIDS	Drug: single dose of L-AmB; Drug: 2 doses of L-AmB; Drug: 2 weeks of L-AmB	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Phase-II Randomized Trial of Three Liposomal Amphotericin B Regimens as Induction Therapy for Disseminated Histoplasmosis in AIDS Patients
• Actual Study Start Date: February 14, 2020
• Actual Primary Completion Date: December 31, 2021
• Actual Study Completion Date: March 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: single dose of L-AmB; single IV dose of 10 mg/kg of L-AmB on day 1;	Drug: single dose of L-AmB; (i) single IV dose of 10 mg/kg of L-AmB on day 1; Other Name: Intervention 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;	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; Other Name: Intervention 2
Active Comparator: 2 weeks of L-AmB; IV dose of 3 mg/kg of L-AmB for 2 weeks.	Drug: 2 weeks of L-AmB; (iii) IV dose of 3 mg/kg of L-AmB for 2 weeks.; Other Name: Intervention 3

Outcome Measures

Primary Outcome Measures :

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

1. Overall mortality [ Time Frame: day 14 ]
   Mortality rates attributed to the cause of death that is not directly and only related to histoplasmosis
2. Mortality due to histoplasmosis [ Time Frame: day 14 ]
   Mortality rates attributed by the study investigator that are directly related to histoplasmosis
3. Renal function abnormalities [ Time Frame: day 14 ]
   Microalbuminuria > 30 mg/24 h
4. 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
5. Histoplasma urinary antigen concentrations [ Time Frame: day 7, 14 ]
   Decrease of at least 50% in Histoplasma urinary antigen concentrations

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Brazil

Irmandade da Santa Casa de Misericórdia de Porto Alegre

Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090

Sponsors and Collaborators

Alessandro Pasqualotto

Hospital de Clinicas de Porto Alegre

Hospital Nossa Senhora da Conceicao

Irmandade Santa Casa de Misericórdia de Porto Alegre

Investigators

• Study Chair: Daiane Dalla Lana, PhD; Federal University of Health Science of Porto Alegre

More Information

• Responsible Party: Alessandro Pasqualotto, Principal Investigator, Federal University of Health Science of Porto Alegre
• ClinicalTrials.gov Identifier: NCT04059770
• Other Study ID Numbers: Three L-AmB Regimens in Histo
• First Posted: August 16, 2019
• Last Update Posted: March 21, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Alessandro Pasqualotto, Federal University of Health Science of Porto Alegre:

Histoplasmosis; AIDS; Liposomal amphotericin B; High dose therapy

Additional relevant MeSH terms:

Histoplasmosis; Mycoses; Bacterial Infections and Mycoses; Infections; Liposomal amphotericin B; Amphotericin B; Antifungal Agents; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Anti-Bacterial Agents