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

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)

Corrección a: Nifurtimox versus benznidazol o placebo para la infección asintomática por Trypanosoma cruzi (Equivalencia de intervenciones habituales para tripanosomiasis - EQUITY): protocolo de estudio para un ensayo controlado aleatorio (vol 20, 431, 2019)

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%)

Predict mortality in a cohort of patients with dilated cardiomyopathy and Chagas Disease Chronic Argentina

Submitted by Gilvan Almeida ([email protected]) on 2016-08-10T18:28:38Z No. of bitstreams: 2 1062.pdf: 1050676 bytes, checksum: 84964785f6e7eda6f9d34bae22e19b10 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Approved for entry into archive by Maria Arruda ([email protected]) on 2018-01-31T14:12:03Z (GMT) No. of bitstreams: 2 1062.pdf: 1050676 bytes, checksum: 84964785f6e7eda6f9d34bae22e19b10 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2018-01-31T14:12:03Z (GMT). No. of bitstreams: 2 1062.pdf: 1050676 bytes, checksum: 84964785f6e7eda6f9d34bae22e19b10 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Introducción y objetivos: El compromiso más avanzado de la Enfermedad de Chagas (ECH) crónica se manifiesta por una miocardiopatía de evolución lenta, progresiva e irreversible, originando discapacidad precoz y muerte temprana. El objetivo principal de este estudio fue analizar predictores de mortalidad en una cohorte de pacientes con ECH y compromiso miocárdico avanzado. Material y método: Se utilizó un diseño de cohortes prospectivo que incluyó 96 pacientes con 2 o 3 técnicas reactivas para Enfermedad de Chagas con dilatación ventricular izquierda y asintomáticos (Estadio II de Kurchnir) o con signos de insuficiencia cardíaca ( Estadio III de Kurchnir). Se incluyeron variables demográficas, clínicas, electro y ecocardiográficas en un análisis tradicional de sobrevida y como punto final la muerte cardiovascular. En el análisis del tiempo de sobrevida se utilizaron las curvas de Kaplan Meier y luego se utilizó un análisis de riesgos proporcionales de Cox hasta encontrar el modelo que mejor ajuste tuvo con mortalidad. Resultados: La media de edad fue de 57 años y fueron seguidos 2.6 años promedio. Treinta de 96 pacientes (28.8%) fallecieron. El grupo fallecido resultó ser significativamente más joven (52 vs 59,p=0.01) .En el análisis de Cox para mortalidad surge la edad como variable protectora (RR:0.96, p =0.039), la clase funcional III –IV (RR:2.39, p= 0.063) y la dilatación de las cavidades derechas (RR:2.41, p= 0.029) Conclusiones: En la Enfermedad de Chagas con compromiso miocárdico es posible determinar mayor riesgo de mortalidad en pacientes jóvenes con inadecuada clase funcional y asociada, al ya presente compromiso izquierdo, la dilatación de las cavidades derechas.Introduction and objectives: The most advanced state of the Cronical Chagas Desease is manifested by a prolonged and irreversible evolution of a myocardiopathy causing in the process early disability and mortality. The main objective of this study was to analyse mortality predictors considering a patient cohort affected by the Chagas Desease with advanced Myocardial Compromise. Material and Method: For the development of the study a prospective cohort design was employed. The analysis considered a total number of 96 patients being subject to an specific treatment based on 2 or 3 reactive techniques and employed for Asymptomatic Chagas Desease involing Left Ventricular Dilation Cardiopathy (Kurchnir´s II state) or Heart Failure signs ( Kurchnir´s III state). In accordance with traditional mortality rate analysis, demographic, clinical, electro and ecocardiographic variables were included. In the Mortality rate analysis were employed Kaplan-Meier curves first and the Cox approach to proportional risk analysis later on in order to adopt the most accurate model represeting Mortality rate results. Result: At study entry, the patients’ mean age was 57 years. They were followed up for a mean of 2.6 years. A number of 30 (28.8 %) out of those total of 96 patients died. The deceased group proved to be significantly much younger (52 vs 59, p=0.01). In the Cox Mortality Analysis appears age as the protective variable (HR:0.96, p=0.039), The functional III – IV Clase (HR: 2.39, p=0.063) and the dilation of the right cavities (HR: 2.41, p=0.029). Conclusions: In the Chagas Desease with myocardial compromise it is possible to determine a higher mortality risk for younger patients with inappropriate functional class as a result of associating the already left compromise, the dilation of the right ventricular and atrial cavities

Chagas cardiomyopathy associated with serological cure after trypanocidal treatment during childhood

Fil: Fernández, Marisa Liliana. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Clínica, Patología y Tratamiento; Argentina.Fil: Hernández, Yolanda. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Clínica, Patología y Tratamiento; Argentina.Fil: Scollo, Karenina. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Diagnóstico; Argentina.Fil: Esteva, Mónica Ines. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Investigación; Argentina.Fil: Riarte, Adelina Rosa. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Clínica, Patología y Tratamiento; Argentina.Fil: Prado, Graciela Nilda. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología. Departamento de Clínica, Patología y Tratamiento; Argentina.Chagas disease is a chronic parasitological disease, which could cause cardiac manifestations in approximately one-third of affected individuals. Benznidazole and nifurtimox are used to treat this parasitological infection caused by Trypanosoma cruzi. Conventionally, the criterion for cure is consistently negative serological tests after treatment. We report a case of a patient who was treated when she was 13 years old and achieved T. cruzi negative seroconversion but developed Chagas disease cardiomyopathy as an adult

Chagas cardiomyopathy associated with serological cure after trypanocidal treatment during childhood

Abstract Chagas disease is a chronic parasitological disease, which could cause cardiac manifestations in approximately one-third of affected individuals. Benznidazole and nifurtimox are used to treat this parasitological infection caused by Trypanosoma cruzi. Conventionally, the criterion for cure is consistently negative serological tests after treatment. We report a case of a patient who was treated when she was 13 years old and achieved T. cruzi negative seroconversion but developed Chagas disease cardiomyopathy as an adult

Use of tissue doppler imaging for the early detection of myocardial dysfunction in patients with the indeterminate form of Chagas disease

Fil: Cianciulli, Tomás Francisco. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Saccheri, María Cristina. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Papantoniou, Alonso. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Méndez, Ricardo José. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Gagliardi, Juan Alberto. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Prado, Nilda Graciela. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Riarte, Adelina. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Morita, Luis Alberto. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Clérici, Javier Eduardo. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Fil: Lax, Jorge Alberto. Division of Cardiology, Hospital del Gobierno de la Ciudad de Buenos Aires "Dr. Cosme Argerich"; Argentina.Chagas disease is one of the most common diseases in Latin America and heart involvement is the main cause of death. This study aimed to determine differences in tissue Doppler imaging (TDI) parameters in the assessment left and right ventricular function in patients with the indeterminate form of Chagas disease compared to those in healthy controls

Corrección a: Nifurtimox versus benznidazol o placebo para la infección asintomática por Trypanosoma cruzi (Equivalencia de intervenciones habituales para tripanosomiasis - EQUITY): protocolo de estudio para un ensayo controlado aleatorio (vol 20, 431, 2019)

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%)

Experimental combination therapy using low doses of benznidazole and allopurinol in mouse models of Trypanosoma cruzi chronic infection

This study evaluated the effectiveness of low doses of benznidazole (BNZ) on continuous administration (BNZc), combined with allopurinol (ALO), in C57BL/6J and C3H/HeN mice infected with Trypanosoma cruzi Nicaragua strain and T. cruzi Sylvio-X10/4 clone. TcN-C57BL/6J was also treated with intermittent doses of BNZ (BNZit). The drug therapy started 3 months post infection (pi) in the chronic phase of mice with heart disease progression, followed-up at 6 months pi. TcN-C57BL/6J treated with BNZc was also monitored up to 12 months pi by serology and electrocardiogram. These mice showed severe electrical abnormalities, which were not observed after BNZc or BNZit. ALO only showed positive interaction with the lowest dose of BNZ. A clear parasitic effect, with significant reductions in antibody titres and parasitic loads, was achieved in all models with low doses of BNZ, and a 25% reduction of the conventional dose showed more efficacy to inhibit the development of the pathology. However, BNZ 75 showed partial efficacy in the TcSylvio-X10/4-C3H/HeN model. In our experimental designs, C57BL/6J allowed to clearly define a chronic phase, and through reproducible efficacy indicators, it can be considered a good preclinical model.Fil: Rial, Marcela Silvina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Scalise, Maria Lujan. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López Alarcón, Maria Micaela. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Bua, Jacqueline Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Benatar, Alejandro Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Prado, Nilda Graciela. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Riarte, Adelina Rosa. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Fichera, Laura Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentin

Speckle tracking echocardiography in the indeterminate form of Chagas disease

Fil: Cianciulli, Tomás Francisco. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Albarracín, Gerardo Ariel. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Napoli Llobera, Mariano. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Prado, Nilda Graciela. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Saccheri, María Cristina. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Hernández Vásquez, Yolanda María. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Méndez, Ricardo José. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Beck, Martín Alejandro. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Baez, Karina Giselle. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Fil: Balletti, Lorena Romina. Hospital of the Government of the City of Buenos Aires "Dr. Cosme Argerich". Division of Cardiology. Echocardiography Laboratory; Argentina.Background: Chagas disease is one of the most common diseases in Latin-America, and cardiac involvement is a significant cause of death. Assessment of myocardial strain may detect early myocardial damage. Objectives: To determine differences in longitudinal strain using speckle tracking to assess regional and global left ventricular function in patients with the indeterminate form of Chagas disease, in comparison with a control group. Methods: This is a retrospective matched case-control study, conducted in a single center. We evaluated 45 adult patients with Chagas disease, diagnosed with 2 serological methods, without evidence of cardiac involvement, who were compared with 45 healthy control subjects, who were sex- and age-matched. All patients underwent Doppler echocardiography and longitudinal strain with speckle tracking. Results: Median age was 59 years, and 60% were female. Echocardiographic parameters were similar in patients with Chagas and control subjects. In patients with Chagas, global strain differed significantly from that of control subjects (-17 vs -20.3, P < .001). Segmental strain showed 7 abnormal segments in patients with Chagas (P < .05). Conclusions: In patients with the indeterminate form of Chagas disease, global and segmental longitudinal peak systolic strain is reduced compared with healthy subjects, thus suggesting that it could be a sensitive technique to detect early myocardial damage. These findings could provide useful information regarding the pathophysiology of cardiac involvement and understand whether they might have prognostic usefulness or help develop strategies to modify the course and prognosis of patients with Chagas disease. A longitudinal prospective study would be necessary to validate our findings