Efficacy and Safety of High-dose Liposomal Amphotericin B for Disseminated Histoplasmosis in AIDS (L-AmB_phase3)

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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Fungal Infection; Immunosuppression; AIDS and Infections; Disseminated Histoplasma Capsulatum Infection
• Intervention / Treatment: Drug: Single high dose of liposomal amphotericin B; Drug: L-AmB standard dose

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.

• Study Type: Interventional
• Enrollment (Estimated): 254
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alessandro C Pasqualotto, MD PhD; Phone Number: +5551999951614; Email: acpasqualotto@hotmail.com
• Study Contact Backup: Name: Diego R Falci, MD PhD; Phone Number: +5551997507835; Email: diego.falci@gmail.com

Study Locations

• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90050-170
      • Federal University of Health Sciences of Porto Alegre
      • Contact: Alessandro C. Pasqualotto, MD PhD; Phone Number: 51999951614; Email: acpasqualotto@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single high dose arm; Single high dose of liposomal amphotericin B (10 mg/kg)	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; Other Names: L-AmB single high dose investigational arm
Active Comparator: Standard dose arm; Standard treatment with 3 mg/kg of liposomal amphotericin B daily for 2 weeks	Drug: L-AmB standard dose; Standard treatment (3 mg/kg for two weeks) with liposomal amphotericin B as induction therapy for disseminated histoplasmosis in AIDS; Other Names: L-AmB conventional therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall mortality (from any cause) will be determined on day 14 of the study	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall mortality (from any cause) will be determined on week 10 of the study	Evaluated on week 10
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Federal University of Health Science of Porto Alegre
• Investigators: Study Chair: Daiane F Dalla Lana, PhD, Federal University of Health Science of Porto Alegre; Study Chair: Renata B Ascenco Soares, PhD, HDT - SES/GO; Study Chair: Luana Bazana, PhD, Federal University of Health Science of Porto Alegre

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): May 28, 2025
• Study Completion (Estimated): May 28, 2026

Study Registration Dates

• First Submitted: March 17, 2023
• First Submitted That Met QC Criteria: April 12, 2023
• First Posted (Actual): April 14, 2023

Study Record Updates

• Last Update Posted (Actual): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: AIDS; Fungal infection; Liposomal amphotericin B; Disseminated Histoplasmosis
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Mycoses; Histoplasmosis; Anti-Infective Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: 67938323.0.1001.5345

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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