- Target disease: Chagas
- Main partners (since project start): Centre de Recerca en Salut Internacional de Barcelona (CRESIB), Spain; Centro de Chagas y Patologia Regional, Hospital Independencia, Argentina; Collective of Applied Studies and Social Development (CEADES), Bolivia; Eisai Co., Ltd., Japan; FP Clinical Pharma – Ethel Feleder, Argentina; Fundacio Investigacio Hospital General Valencia, Spain; Fundación Mundo Sano and Laboratorio ELEA PHOENIX, Argentina; Hospital de Niños Dr Ricardo Gutiérrez, Argentina; IS Global, Institute for Global Health, Spain; Instituto Nacional de Epidemiología Dr Fatala Cháben, Argentina; LAT Research, Argentina; Luxembourg Institute of Health, Luxembourg; National Council of Scientific and Technological Research (INGEBI-CONICET), Argentina; NUDFAC – Nucleus of Pharmaceutical and Cosmetics Development, Brazil; PhinC, France; Platform of Integral Care for Patients with Chagas Disease, Spain/Bolivia; Universidad Autónoma Juan Misael Saracho, Bolivia; Universidad Mayor de San Simon, Bolivia.
- Project start: December 2013
- Funding (since project start): Department for International Development (DFID), UK; Federal Ministry of Education and Research (BMBF through KfW), Germany; Global Health Innovative Technology (GHIT) Fund, Japan; Médecins Sans Frontières/Doctors without Borders, International; Ministry of Foreign Affairs (DGIS), The Netherlands; Rockefeller Foundation, USA; Swiss Agency for Development and Cooperation (SDC), Switzerland; Starr International Foundation, Switzerland.
Benznidazole, the current Chagas treatment, is effective but has limitations: it lasts 60 days, and some 20% of patients stop treatment due to side effects, which include gastric intolerance, skin rashes, or neuromuscular problems. To explore whether these were related to dose or treatment duration, DNDi decided to test the efficacy of new regimens where exposure to benznidazole would be reduced, either due to shorter treatment, lower doses, or both.
In 2013, a proof-of-concept trial showed that fosravuconazole, an azole-class antifungal drug discovered by Eisai, had good safety and was effective at clearing the parasite, but efficacy was not sustained. A Phase I drug-drug interaction study assessed the safety and pharmacokinetic interactions of fosravuconazole and benznidazole administered separately and in combination. No major clinically relevant safety or tolerability issues were identified. A Phase II, randomized, placebo-controlled study was carried out in three sites in Bolivia between 2016 and 2018. It tested, against a placebo, six benznidazole treatments of differing lengths and dosages, both as a monotherapy and in combination with fosravuconazole. The aim was to improve efficacy, safety, and tolerability of treatment of adults with chronic indeterminate Chagas. Results showed that the new regimens presented good safety profile. DNDi will now continue to work with national programmes, partners, and health ministries of endemic countries to confirm these results and encourage the necessary steps to register the new regimen.
The results, available in early 2019, showed that all treatment arms were effective compared to placebo and the new regimens presented good safety profiles. The two-week course of treatment was particularly promising. While significantly shorter than the standard eight-week treatment, it showed 83% of efficacy and none of the patients assigned to this arm had to discontinue treatment due to side effects. The primary measure of efficacy for this study was sustained parasitological response at six months’ follow-up with a final assessment at 12 months.
This proof-of-concept trial was completed in the third quarter of 2018 and results will be available in early 2019. A total of 210 patients were recruited for this study, which was conducted in three sites in Bolivia and aims to improve efficacy, safety and tolerability of treatment of adults with chronic indeterminate Chagas. The trial assessed the efficacy of different doses of benznidazole in monotherapy and in combination with fosravuconazole. The primary measure of efficacy is a sustained parasitological response at six months follow-up with a final assessment at 12 months.
The trial is being conducted in three sites in Bolivia, with recruitment completed in late 2017. The primary efficacy parameter is sustained parasitological response at six months. The final assessment will include 12 months of follow-up, with final results available in early 2019.
Regulatory approvals were secured in Bolivia to start a Phase II Proof of Concept (PoC) study to determine if the safety (known as the “BENDITA” study) and tolerability issues of benznidazole could be managed by reduced doses and treatment duration, or by combining it with fosravuconazole. Benznidazole in monotherapy or in combination with fosravuconazole at selected doses and treatment durations will be assessed versus placebo in 210 patients with chronic Chagas disease. Recruitment started at the end of November; 10 patients had been enrolled by the end of 2016.
Last update: August 2019