New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial.

BACKGROUND: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. METHODS: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18-50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. FINDINGS: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73-99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73-99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64-95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65-95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67-97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64-95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. INTERPRETATION: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. FUNDING: Drugs for Neglected Diseases initiative (DNDi). TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Challenges in a product development partnership: a malaria treatment case study. / Desafios de uma parceria para o desenvolvimento de produtos: o caso de um tratamento para malária.

This paper examines the development of a treatment - a fixed-dose combination of artesunate and mefloquine - in Brazil, from three points of view: in terms of access to medication; to record and report successes; and to look at the lessons learned. This product development took place in the ambit of a public-private partnership. Semi-structured interviews were held with key actors involved in the different phases of the development, and documents were analyzed. Two important points of reference orienting the design of the study and analysis were: a logical model for access to medication; and evaluation of programs. It is concluded that there were several successes over the course of the project, but insufficient attention was given in the project's architecture to planning of adoption of the product: irregularities in demand caused difficulties in planning and production, and adoption of the product was irregular in the Americas. It is concluded that the project can be considered to have been successful: the product was created, and the aims were met - strengthening of institutional and individual capacities and alliances, and advocacy. However, there were weaknesses in the process, which need to be mitigated in future projects of the same type.

Desafios de uma parceria para o desenvolvimento de produtos: o caso de um tratamento para malária / Challenges in a product development partnership: a malaria treatment case study

Analisou-se o processo de desenvolvimento da combinação em dose fixa de artesunato e mefloquina no Brasil à luz de dimensões do acesso a medicamentos, visando registrar acertos e lições aprendidas. Tratou-se de um estudo de caso do desenvolvimento de produto no âmbito de uma parceria público privada. Foram realizadas entrevistas semiestruturadas com atores-chave envolvidos nas diferentes etapas do desenvolvimento e analisados documentos. Modelo lógico de acesso aos medicamentos assim como avaliação de programas foram importantes referenciais que orietaram o desenho do estudo e a análise. A despeito dos vários acertos ao longo do trabalho, o planejamento da adoção do produto foi insuficientemente contemplado na arquitetura do projeto em análise, irregularidades na demanda geraram dificuldades no planejamento da produção do produto, que tem adoção irregular na região das Americas. O projeto pode ser considerado bem sucedido, tendo sido alcançado o produto e atendidos os pilares propostos de fortalecimento de capacidades e alianças tanto institucionais quanto individuais e advocacy. No entanto, foi possível registrar fragilidades do processo a serem mitigadas em projetos futuros de mesma natureza.

A saúde na agenda da política externa brasileira nos governos dos presidentes Fernando Henrique Cardoso (1995 - 2002) e Luiz Inácio Lula da Silva (2003 - 2010) / Health in Brazil's foreign policy agenda in the administrations of Presidents Fernando Henrique Cardoso (1995 - 2002) and Luiz Inácio Lula da Silva (2003 - 2010)

O presente trabalho tem por objetivo realizar o diálogo entre os temas de saúde e política externa a partir do caso brasileiro durante os governos dos presidentes Fernando Henrique Cardoso (1995-2002) e Luiz Inácio Lula da Silva (2003-2010). Por meio da análise das diretrizes da política externa brasileira entre 1995 e 2010, busca-se identificar o porquê do processo de institucionalização do tema da saúde na agenda da política externa do país, considerando-se a hipótese de que a saúde era um tema de importância estratégica para o objetivo maior da diplomacia brasileira, qual seja a participação influente na política internacional. Para tanto, discute-se os conceitos de saúde global e diplomacia em saúde, as formas de interação entre a saúde e outras dimensões da política externa e o papel das ideias na formulação dessa política de acordo com a abordagem construtivista da Teoria de Relações Internacionais. Além disso, as mudanças político-administrativas nas estruturas do Ministério da Saúde e do Ministério das Relações Exteriores e as referências à saúde nos discursos políticos das autoridades brasileiras, especialmente dos presidentes da República, foram utilizadas para a ilustração do referido processo de institucionalização. A articulação significativa entre essas pastas ministeriais e a proeminência do Ministério da Saúde nas políticas internacionais em saúde também são analisadas na evolução da diplomacia em saúde do Brasil e sua projeção como uma referência global em saúde. Nota-se o fortalecimento do tema da saúde na agenda da diplomacia brasileira, apesar das diferenças nos estilos de política externa dos presidentes mencionados...

This study explores the dialogue between health and foreign policy under theadministrations of Presidents Fernando Henrique Cardoso (1995-2002) and Luiz InácioLula da Silva (2003-2010). Through an analysis of the contours and priorities ofBrazilian foreign policy between 1995 and 2010, it aims to identify the reasons of theprocess through which health issues were institutionalized as part of the Braziliandiplomatic agenda. Specifically, it sets out the hypothesis that health is a topic ofstrategic importance to the primary goal of Brazilian foreign policy, which is influentialparticipation in international politics. To this end, the research discusses the concepts ofglobal health and health diplomacy, interaction between health and other dimensions offoreign policy, and the role of ideas in the formulation of this policy in accordance withthe constructivist approach of International Relations Theory. Moreover, the politicaland administrative changes in the structures of the Ministries of Health and ForeignAffairs, as well as references to health in Brazilian political discourse, especially that ofthe presidents of the Republic, were employed to illustrate the process ofinstitutionalization. The significant link between these Ministries and the prominence ofthe Ministry of Health in international health policies are also analyzed in the evolutionof Brazil’s health diplomacy and the country’s projection as a global health leader.Despite the differences in styles of foreign policy between Fernando Henrique Cardosoand Lula da Silva, the importance of health as a part of Brazil’s foreign policy agendawas significant over the period examined...