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

Villar, Juan Carlos; Herrera, Víctor M.; Carreño, Juan Guillermo Pérez; Herrera, Eliana Váquiro; Castellanos-Domínguez, Yeny Zulay; Vásquez, Skarlet Marcell; Cucunubá, Zulma M.; Prado, Nilda Graciela; Hernández, Yolanda

doi:10.1186/s13063-019-3630-y

Cited by 4 publications

(3 citation statements)

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“…To overcome the initial barrier of large loss-to-follow-up rates, it is possible to consider external information, such as the small rate of seroreversion when patients are untreated (henceforth referred to as spontaneous seroreversion ). For instance, two studies in children report a rate of about 5% [ 17 , 18 ], while a meta-analysis of studies in adults reports a rate as low as 2% [ 19 ]. The significance of these low rates becomes clear when compared to the most conservative imputation strategy for the missing NFX patients.…”

Section: Case Study: the Effectiveness Of Nifurtimox In The Treatment...mentioning

confidence: 99%

“…Prespecification of the analysis must include the range of plausible values for the sensitivity parameter, which may be based on prior literature or consensus in the substantive field. For instance, a prespecified analysis plan for the case study of the effect of Nifurtimox on the Chagas disease may have conservatively prespecified 10% as the maximum possible rate of spontaneous seroreversion among the treated, based on prior literature that suggests that this rate is of at most 5% [17][18][19].…”

Section: Prespecificationmentioning

confidence: 99%

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Sensitivity analysis for causality in observational studies for regulatory science

Díaz,

Lee,

Kıcıman

et al. 2023

J. Clin. Trans. Sci.

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Objective: The United States Congress passed the 21st Century Cures Act mandating the development of Food and Drug Administration guidance on regulatory use of real-world evidence. The Forum on the Integration of Observational and Randomized Data conducted a meeting with various stakeholder groups to build consensus around best practices for the use of real-world data (RWD) to support regulatory science. Our companion paper describes in detail the context and discussion of the meeting, which includes a recommendation to use a causal roadmap for study designs using RWD. This article discusses one step of the roadmap: the specification of a sensitivity analysis for testing robustness to violations of causal model assumptions. Methods: We present an example of a sensitivity analysis from a RWD study on the effectiveness of Nifurtimox in treating Chagas disease, and an overview of various methods, emphasizing practical considerations on their use for regulatory purposes. Results: Sensitivity analyses must be accompanied by careful design of other aspects of the causal roadmap. Their prespecification is crucial to avoid wrong conclusions due to researcher degrees of freedom. Sensitivity analysis methods require auxiliary information to produce meaningful conclusions; it is important that they have at least two properties: the validity of the conclusions does not rely on unverifiable assumptions, and the auxiliary information required by the method is learnable from the corpus of current scientific knowledge. Conclusions: Prespecified and assumption-lean sensitivity analyses are a crucial tool that can strengthen the validity and trustworthiness of effectiveness conclusions for regulatory science.

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Section: Case Study: the Effectiveness Of Nifurtimox In The Treatment...mentioning

confidence: 99%

Section: Prespecificationmentioning

confidence: 99%

Sensitivity analysis for causality in observational studies for regulatory science

Díaz,

Lee,

Kıcıman

et al. 2023

J. Clin. Trans. Sci.

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show abstract

“…Although the Romaña sign (periorbital swelling syndrome) is characteristic in children bitten by insects (Da Costa et al, 2020; Lescure et al, 2008), most symptoms in the acute phase of the disease are nonspecific, which complicates the diagnosis, as the site of the bite is normally not evident (Colombo et al, 2021; Crespillo‐Andújar et al, 2018; Howard et al, 2014). Besides the loss of effectiveness of first‐line medications in later stages of the disease (Ciapponi et al, 2020; Forsyth et al, 2016; Jackson et al, 2020; Soares et al, 2021), nearly 40% of patients experience side effects of these drugs, exerting a negative impact on adherence to treatment, which takes approximately 2 months (Carlos Villar et al, 2019; Crespillo‐Andújar et al, 2018; Crespillo‐Andújar et al, 2020; Pérez‐Molina et al, 2021; Scarim et al, 2018; Villar et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Structure‐based design, optimization of lead, synthesis, and biological evaluation of compounds active against Trypanosoma cruzi

de Almeida,

de Oliveira,

da Silva Monte

et al. 2023

Chem Biol Drug Des

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Chagas' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease–Trypanosoma cruzi–has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4‐amino‐5‐carbonitrile‐pyrimidine analogues were proposed, synthesized (5a‐f and 7g‐h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC50 = 2.79 ± 0.00 μM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain.

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Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

Ciapponi

Barreira²,

Perelli

et al. 2022

Tropical Med Int Health

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Objectives To determine the comparative efficacy and safety of a fixed dose of benznidazole (BZN) with an adjusted‐dose for Trypanosoma cruzi‐seropositive adults without cardiomyopathy. Methods We conducted a systematic review and individual participant data (IPD) meta‐analysis following Cochrane methods, and the PRISMA‐IPD statement for reporting. Randomised controlled trials (RCTs) allocating participants to fixed or adjusted doses of BZN for T. cruzi‐seropositive adults without cardiomyopathy were included. We searched (December 2021) Cochrane, MEDLINE, EMBASE, LILACS and trial registries and contacted Chagas experts. Selection, data extraction, risk of bias assessment using the Cochrane tool, and a GRADE summary of finding tables were performed independently by pairs of reviewers. We conducted a random‐effects IPD meta‐analysis using the one‐stage strategy, or, if that was impossible, the two‐stage strategy. Results Five RCTs (1198 patients) were included, none directly comparing fixed with adjusted doses of BZN. Compared to placebo, BZN therapy was strongly associated with negative qPCR and sustainable parasitological clearance regardless of the type of dose and subgroup analysed. For negative qPCR, the fixed/adjusted rate of odds ratios (RORF/A) was 8.83 (95% CI 1.02–76.48); for sustained parasitological clearance, it was 4.60 (95% CI 0.40–52.51), probably indicating at least non‐inferior effect of fixed doses, with no statistically significant interactions by scheme for global and most subgroup estimations. The RORF/A for treatment interruption due to adverse events was 0.44 (95% CI 0.14–1.38), probably indicating no worse tolerance of fixed doses. Conclusions We found no direct comparison between fixed and adjusted doses of BZN. However, fixed doses versus placebo are probably not inferior to weight‐adjusted doses of BZN versus placebo in terms of parasitological efficacy and safety. Network IPD meta‐analysis, through indirect comparisons, may well provide the best possible answers in the near future. Registration The study protocol was registered in PROSPERO (CRD42019120905).

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

Cited by 4 publications

References 1 publication

Sensitivity analysis for causality in observational studies for regulatory science

Sensitivity analysis for causality in observational studies for regulatory science

Structure‐based design, optimization of lead, synthesis, and biological evaluation of compounds active against Trypanosoma cruzi

Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

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