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Randomized Trial of Liposomal Amphotericin B for Histoplasmosis in AIDS Patients

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ClinicalTrials.gov Identifier: NCT04059770
Recruitment Status : Recruiting
First Posted : August 16, 2019
Last Update Posted : July 16, 2021
Sponsor:
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

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Histoplasmosis

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




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



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04059770


Contacts
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Contact: Alessandro C. Pasqualotto, MD PhD 55 51 999951614 acpasqualotto@hotmail.com
Contact: Cássia Caurio 55 51 995888081 cassiacaurio@hotmail.com

Locations
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Brazil
Irmandade da Santa Casa de Misericórdia de Porto Alegre Recruiting
Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090
Contact: Alessandro Pasqualotto, Dr         
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
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Study Chair: Daiane Dalla Lana, PhD Federal University of Health Science of Porto Alegre
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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    Key Record Dates
Last Update Posted: July 16, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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