Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial.

Publisher: BioMed Central Country of Publication: England NLM ID: 101263253 Publication Model: Electronic Cited Medium: Internet ISSN: 1745-6215 (Electronic) Linking ISSN: 17456215 NLM ISO Abbreviation: Trials Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2006-

Chagas Disease/*drug therapy ; Nifurtimox/*therapeutic use ; Nitroimidazoles/*therapeutic use ; Trypanocidal Agents/*therapeutic use ; Trypanosoma cruzi/*drug effects; Adult ; Aged ; Asymptomatic Diseases ; Chagas Disease/diagnosis ; Chagas Disease/parasitology ; Colombia ; Female ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Nifurtimox/adverse effects ; Nitroimidazoles/adverse effects ; Randomized Controlled Trials as Topic ; Therapeutic Equivalency ; Time Factors ; Treatment Outcome ; Trypanocidal Agents/adverse effects ; Trypanosoma cruzi/pathogenicity ; Young Adult

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.

Erratum in: Trials. 2019 Aug 20;20(1):516. (PMID: 31429793)

Int J Epidemiol. 2001 Aug;30(4):894-5. (PMID: 11511623)
Rev Inst Med Trop Sao Paulo. 2002 Jan-Feb;44(1):29-37. (PMID: 11896410)
BMJ. 2007 Aug 11;335(7614):269-70. (PMID: 17690342)
PLoS Negl Trop Dis. 2009 Jul 07;3(7):e488. (PMID: 19582142)
PLoS Negl Trop Dis. 2011 Jan 11;5(1):e931. (PMID: 21264349)
Mem Inst Oswaldo Cruz. 2011 Sep;106(6):641-5. (PMID: 22012216)
Antimicrob Agents Chemother. 2013 Jan;57(1):390-5. (PMID: 23114763)
N Engl J Med. 2014 May 15;370(20):1899-908. (PMID: 24827034)
PLoS Negl Trop Dis. 2014 May 22;8(5):e2907. (PMID: 24853169)
Cochrane Database Syst Rev. 2014 May 27;(5):CD003463. (PMID: 24867876)
PLoS Negl Trop Dis. 2015 Feb 27;9(2):e0003465. (PMID: 25723465)
J Mol Diagn. 2015 Sep;17(5):605-15. (PMID: 26320872)
N Engl J Med. 2015 Oct;373(14):1295-306. (PMID: 26323937)
Antimicrob Agents Chemother. 2015 Nov 23;60(2):833-7. (PMID: 26596935)
Perspect Public Health. 2017 Sep;137(5):289-295. (PMID: 27758973)
J Am Coll Cardiol. 2017 Feb 28;69(8):939-947. (PMID: 28231946)
Rev Soc Bras Med Trop. 2017 Nov-Dec;50(6):748-755. (PMID: 29340450)
Lancet Infect Dis. 2018 Apr;18(4):419-430. (PMID: 29352704)
Lancet. 1996 Nov 23;348(9039):1407-13. (PMID: 8937280)
Rev Soc Bras Med Trop. 1997 Mar-Apr;30(2):139-44. (PMID: 9148337)
Am J Trop Med Hyg. 1998 Oct;59(4):526-9. (PMID: 9790423)

MR/R015600/1 United Kingdom MRC_ Medical Research Council; Research contract 729-2013 Colciencias

Keywords: Benznidazole; Chagas disese; Nifurtimox; Randomized controlled trial; Trypanosoma cruzi

ClinicalTrials.gov NCT02369978

0 (Nitroimidazoles)
0 (Trypanocidal Agents)
M84I3K7C2O (Nifurtimox)
YC42NRJ1ZD (benzonidazole)

Date Created: 20190717 Date Completed: 20200205 Latest Revision: 20210110

20240105

PMC6631895

10.1186/s13063-019-3423-3

31307503