R01AI181764

Liposomal Amphotericin B and Flucytosine Antifungal Strategies for Talaromycosis (LAMB-FAST) - Abstract

Talaromycosis is caused by the dimorphic fungus Talaromyces marneffei (TM) endemic in Southeast Asia where it is a leading cause of death among patients with advanced HIV disease with a mortality on treatment of 30%.

Treatment options are limited to just two drugs: Amphotericin B deoxycholate (DAMB) which has substantial toxicity and Itraconazole which has poor bioavailability.

Our research team has recently delivered the landmark IVAP trial demonstrating the superiority of DAMB over Itraconazole in survival and rate of fungal clearance, propelling DAMB as the first-line therapy in 2019.

Although highly potent, DAMB infusion over 14 days is associated with serious toxicity; hence the drug has largely been abandoned in high-income countries.

As a roadmap to identify safer and more effective antifungal strategies, our proposal applies three major advances made in AIDS-associated mycoses to accelerate treatment for Talaromycosis.

First, clinical trials in cryptococcosis show that shorter (5-7 days) courses of DAMB are as effective but less toxic than the standard 14-day course.

Second, the AMBITION trial has shown that a single 10 mg/kg dose of liposomal Amphotericin B (LAMB) is as effective as 7-14 days of DAMB but has 30% less toxicity, leading to rapid endorsement by the WHO as the first-line therapy for cryptococcal meningitis in 2022.

Third, addition of Flucytosine (5FC) to DAMB has been shown to be safe, improves fungal clearance and survival.

These advances in cryptococcosis lead us to hypothesize that 1) a single 10 mg/kg dose of LAMB will be superior to 14 days of DAMB and 2) the addition of 5FC will be superior to DAMB or LAMB alone in TM complication-free survival.

We will build on our experience in leading the five-center IVAP trial in Vietnam to conduct a factorial, partially placebo-controlled trial to test two hypotheses within one LAMB-FAST trial, thus cutting time to knowledge and cost by half.

We propose three related but independent specific aims:

Aim 1. Determine if a single 10 mg/kg dose of LAMB is superior to 14 days of DAMB in TM complication-free survival.

Aim 2. Determine if combination therapy with 5FC is superior to DAMB or LAMB alone in TM complication-free survival.

The primary outcome for both aims 1 and 2 is hazard of a composite of death, TM complications, and AEs grade 3 or higher.

Secondary outcomes include: 1) all-cause mortality; 2) fungal clearance rate over first 14 days; 3) a novel 4-scale hierarchical outcome of I. mortality, II. TM complications, III. AE grade 3, IV. quality of life scores; 4) rates of TM DNA and TM antigen decline over first 12 weeks.

In Aim 3, we will leverage rare access to a well-characterized and treated Talaromycosis cohort to conduct a follow-on nested randomized controlled sub-study testing whether a HIV viral load guided strategy of stopping Itraconazole chemoprophylaxis (STOP SHORT) is non-inferior to the current CD4 guided strategy in the prevention of Talaromycosis relapse and death.

Impact statement. The results of this trial are likely to change treatment guidelines for Talaromycosis.

Duke University

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Durham, North Carolina 277103038 United States

Single Zip Code

Investigator Initiated Extended Clinical Trial (R01 Clinical Trial Required) (PAR-23-084)

Amendment Since initial award the total obligations have increased 225% from $1,195,494 to $3,889,270.