Villar et al. Trials (2019) 20:431 https://doi.org/10.1186/s13063-019-3423-3 STUDY PROTOCOL Open Access Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial Juan Carlos Villar1,2* , Víctor Mauricio Herrera1, Juan Guillermo Pérez Carreño2,3, Eliana Váquiro Herrera2, Yeny Zulay Castellanos Domínguez1, Skarlet Marcell Vásquez1, Zulma Milena Cucunubá4,5, Nilda Graciela Prado6 and Yolanda Hernández6 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. ThetrialoutsideColombia(expectedtorecruitatleast60%of participants) is pragmatic; it may be open-label and not includealltreatmentgroups,butitmustadheretotherandomisation 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%). (Continued on next page) * Correspondence: [email protected] 1Grupo de Cardiología Preventiva, Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga, Calle 157 No 19- 55, Campus el Bosque, Bucaramanga, Colombia 2Departamento de Investigaciones, Fundación Cardioinfantil- Instituto de Cardiología, Bogotá, Colombia Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Villar et al. Trials (2019) 20:431 Page 2 of 10 (Continued from previous page) 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. Keywords: Nifurtimox, Benznidazole, Trypanosoma cruzi, Chagas disese, Randomized controlled trial Background Outcomes of Chagas disease (CHICAMOCHA 3) pro- The World Health Organization (WHO) estimates that ject, the Equivalence of Usual Interventions for Tryp- 8 million people are infected by Trypanosoma cruzi, the anosomiasis (EQUITY) trial. parasite causing Chagas disease, and 10,000 of these people are expected to die every year [1]. Different Methods health authorities recommend either nifurtimox (NFX) Overall, the aim of the EQUITY trial is to evaluate, or benznidazole (BZN) as treatment for T. cruzi-infected T. cruzi – among young adults with chronic infection but individuals [2 5]. The purpose of using these trypanoci- no symptomatic chronic Chagas cardiomyopathy, the dal agents is to reduce the parasitic load (expecting to trypanocidal effect and safety of a treatment with NFX prevent, delay or reduce the impact of clinical complica- compared with BZN or placebo. tions) and to reduce its transmission [6]. However, a number of reasons hinder this potential opportunity. Firstly, convincing evidence of efficacy from randomised Study design trials is limited to parasite-related (but not patient- We will conduct a randomised, concealed, multi-centre, important) outcomes [7], to treatment with BZN (but not parallel-group, blind trial, testing the superiority of NFX) and to individuals from Brazil and Argentina and NFX over placebo and its non-inferiority compared more recently Bolivia (but not other countries in Latin with BZN. America) [8–13]. Secondly, the tolerance to this treat- ment, typically offered for 60–90 days, is still suboptimal, Setting and participants with an abandon rate ranging from10 to 20% reported in EQUITY will seek collaborating centres from Colombia these studies. and other countries in Latin America offering care to In the above context, decision-makers, at both the outpatients with T. cruzi chronic infection. Study centres individual and population levels, will benefit from more will be actively seeking eligible candidates with local information on the efficacy and safety of NFX as treat- centres for serology diagnosis, blood banks or health ment for T. cruzi infection. The trypanocidal effect of authorities. The eligible population will be individuals NFX, demonstrated in a single trial in Brazil [14], needs aged 20–65 of both sexes, with serology diagnosis (posi- replication and validation in other populations. Further- tive results for at least two out of three serological tests more, treatment with BZN in the BENEFIT trial proved including enzyme-linked immunosorbent assay [ELISA] to be trypanocidal for participants from Argentina and and indirect immunofluorescence of haemagglutination Brazil (80% of the study population) but not for (the over the last 10 years), negligible risk of re-infection remaining 20%, 502 and 78) participants from Colombia (residence in an urban setting or a suburban/rural area and El Salvador [11]. Geographical variability of trypano- with no history of vector infestation or transmission) cidal efficacy of BZN had been previously reported in a and the capability to attend regular follow-up visits at large case series of school children from Bolivia, the study centres (Table 1). Honduras and Guatemala [15]. This highlights the Exclusion criteria include the following: previous treat- importance of expanding the existing information on the ment with BZN or NFX or participation in trials testing trypanocidal efficacy of NFX and exploring its equiva- trypanocidal drug candidates; any symptom suggesting lence to BZN. This emerging information may be of par- chronic Chagas (or other forms) of cardiomyopathy or ticular interest for endemic countries with smaller uncontrolled risk factors for it; persistent abnormalities representation in previous trials, such as Colombia. in liver/kidney blood function tests (alanine amino In the direction of addressing this research gap, this transferase [ALAT]/aspartate amino transferase [ASAT] paper describes the methods for Phase 3 of the Cardio- twofold normal values or creatinine over 1.2 mg/dl vascular Health Investigation and Collaboration from observed at least twice); women of childbearing age who Countries of America to Assess the Markers and have positive pregnancy tests or are unwilling to use Villar et al. Trials (2019) 20:431 Page 3 of 10 secure birth control methods; or any concomitant health participants and their relatives, treating physicians and problem judged by the study physician as potentially study teams, the study medication will be packaged in a interfering with free participation, health or well-being similar fashion. We used similar gelatin capsules to in- during the study or administration of treatment. clude and mask the contents of the original tablets of ac- tive treatments or placebo (a mix of microcrystalline Interventions cellulose and magnesium stearate), as shown in Fig. 2. The randomly allocated study interventions may differ The study medication was packed in bottles of 120 cap- for centres across countries. While in Colombia sules (intended to last for 2 months) labelled with the EQUITY will offer masked (i.e. similar-looking) treat- study name and treatment codes, making the study arms ments, including placebo or active treatments, in the indistinguishable from each other. remaining centres it