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Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): Study protocol for a randomised controlled trial
Título de la revista
Autores
Villar, Juan Carlos
Herrera, Víctor Mauricio
Pérez Carreño, Juan Guillermo
Váquiro Herrera, Eliana
Castellanos Domínguez, Yeny Zulay
Vásquez, Skarlet Marcell
Cucunubá, Zulma Milena
Prado, Nilda Graciela
Hernández, Yolanda
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Fecha
2019
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BioMed Central Ltd.
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Abstract
Background: Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. Methods: The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20-65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12-18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ? 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ? 25% with NFX to claim its trypanocidal effect, 60-80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80-90% power; one-sided alpha level 1%). Discussion: The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents. Trial registration: ClinicalTrials.gov, NCT02369978. Registered on 24 February 2015. © 2019 The Author(s).
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Keywords
Benznidazole , Nifurtimox , Placebo , Antitrypanosomal agent , Benznidazole , Nifurtimox , Nitroimidazole derivative , Adult , Adverse outcome , Aged , Article , Chagas disease , Controlled study , Disease severity , Drug efficacy , Drug safety , Dyspepsia , Female , Headache , Human , Major clinical study , Male , Medication compliance , Multicenter study , Neuropathic pain , Paresthesia , Polymerase chain reaction , Randomized controlled trial , Serology , Skin manifestation , Therapy effect , Treatment duration , Treatment outcome , Treatment refusal , Trypanosomiasis , Asymptomatic disease , Chagas disease , Colombia , Drug effect , Middle aged , Multicenter study (topic) , Parasitology , Pathogenicity , Randomized controlled trial (topic) , Therapeutic equivalence , Time factor , Trypanosoma cruzi , Young adult , Adult , Aged , Asymptomatic diseases , Chagas disease , Colombia , Female , Humans , Male , Middle aged , Multicenter studies as topic , Nifurtimox , Nitroimidazoles , Randomized controlled trials as topic , Therapeutic equivalency , Time factors , Treatment outcome , Trypanocidal agents , Trypanosoma cruzi , Young adult , Benznidazole , Chagas disese , Nifurtimox , Randomized controlled trial , Trypanosoma cruzi
