Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial

<div><p>Background</p><p>There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.</p><p>Methods</p><p>A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb⁺⁵/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb⁺⁵/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.</p><p>Results</p><p>378 patients were randomized to the four treatment arms<b>:</b> MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).</p><p>Conclusions</p><p>Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01310738" target="_blank">NCT01310738</a></p></div

CONSORT patient flowchart.

<p>Flow diagram of the progress through the phases of the trial. AmphoB = amphotericin B deoxycholate; MA = meglumine antimoniate; LAMB = Liposomal amphotericin B.</p

Early withdrawal rate due to the occurrence of AE/SAE during treatment as per ITT.

<p>Early withdrawal rate due to the occurrence of AE/SAE during treatment as per ITT.</p

Frequency of AE and SAE related to study medication, and temporary and definitive treatment suspension due to the occurrence of AE per intervention arm.

<p>Frequency of AE and SAE related to study medication, and temporary and definitive treatment suspension due to the occurrence of AE per intervention arm.</p

Treatment efficacy at six months follow-up as PP approach.

<p>Treatment efficacy at six months follow-up as PP approach.</p

Survival time until fever clearance.

<p>Survival time until fever clearance per treatment arm by the Kaplan Meier method. MA = meglumine antimoniate; LAMB = Liposomal amphotericin B.</p

Proportion of participants presenting at least one related AE, SAE and AE grade 3 and 4 per intervention arm.

<p>Proportion of participants presenting at least one related AE, SAE and AE grade 3 and 4 per intervention arm.</p

Núcleos de Ensino da Unesp: artigos 2011: volume 3: tecnologias da informação e comunicação e material pedagógico

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP