Efficacy and Safety of High-dose Liposomal Amphotericin B for Disseminated Histoplasmosis in AIDS

Immunosuppression Clinical Trial

Official title:

Efficacy and Safety of High-dose Liposomal Amphotericin B (10 mg/kg) for Disseminated Histoplasmosis in AIDS: a Randomized Phase III Trial (INDUCTION Trial)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05814432
• Other study ID #: 67938323.0.1001.5345
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: March 1, 2024
• Est. completion date: May 28, 2026

Study information

• Verified date: February 2024
• Source: Federal University of Health Science of Porto Alegre
• Contact: Alessandro C Pasqualotto, MD PhD
• Phone: +5551999951614
• Email: acpasqualotto[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Not yet recruiting
• Enrollment: 254
• Est. completion date: May 28, 2026
• Est. primary completion date: May 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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
• Presence of fever in addition to one of the following: weight loss (>10% of usual body weight), diarrhea, miliary pattern on thorax imaging, pancytopenia, lymphadenopathy, splenomegaly, or hepatomegaly

Exclusion criteria:

• Refusal to participate in the trial
• Previous diagnosis of histoplasmosis
• Pregnant or lactating women
• Renal impairment (serum creatinine or urea >1.5x the upper limit of normal)
• 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 diagnosed with tuberculosis (molecularly or microbiologically) at baseline will be excluded, as rifampicin prohibitively interacts with itraconazole; in addition, patients receiving drugs that cause significant drug interaction (relative or absolute) with Itraconazole, will be excluded.

Related Conditions & MeSH terms

• AIDS and Infections
• Communicable Diseases
• Fungal Infection
• Histoplasmosis
• Immunosuppression
• Infections
• Mycoses

Intervention

Drug:
• Single high dose of liposomal amphotericin B
Single high dose (10 mg/kg) of liposomal amphotericin B as induction therapy for disseminated histoplasmosis in AIDS
• L-AmB standard dose
Standard treatment (3 mg/kg for two weeks) with liposomal amphotericin B as induction therapy for disseminated histoplasmosis in AIDS

Locations

Country	Name	City	State
Brazil	Federal University of Health Sciences of Porto Alegre	Porto Alegre	Rio Grande Do Sul

Sponsors (1)

Lead Sponsor	Collaborator
Federal University of Health Science of Porto Alegre

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Overall mortality (from any cause) will be determined on day 14 of the study	14 days
Secondary	Overall survival	Overall mortality (from any cause) will be determined on week 10 of the study	Evaluated on week 10
Secondary	Clinical response	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.	Evaluated on day 14
Secondary	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	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.	Evaluated on day 14
Secondary	Desirability of Outcome Ranking (DOOR) score	Categorized as follows: (i) Death within the first two weeks of randomization; (ii) Death within the 10-week follow-up period; (iii) Grade 4 laboratory abnormality in the first two weeks (electrolytes, anemia/leukopenia, or renal dysfunction); (iv) Grade 3 laboratory abnormality in the first two weeks (electrolytes, anemia/leukopenia, or renal dysfunction); and (v) Survival at week 10.	Evaluated on week 10
Secondary	Treatment effect on Histoplasma urinary antigen levels	The effect of at least a 50% decrease in Hisroplasma urinary antigen concentrations over the first two weeks of therapy will be determined.	Evaluated on day 14
Secondary	Treatment impact on qPCR result	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.	Evaluated on day 14