Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II superiority clinical trial

Abstract

Background: Chagas disease (CD) continues to be a neglected infectious disease with one of the largest burdens globally. Despite the modest cure rates in adult chronic patients and its safety profile, benznidazole (BNZ) is still the drug of choice. Its current recommended dose is based on nonrandomized studies, and efficacy and safety of the optimal dose of BNZ have been scarcely analyzed in clinical trials.Methods/design: MULTIBENZ is a phase II, randomized, noninferiority, double-blind, multicenter international clinical trial. A total of 240 patients with Trypanosoma CD in the chronic phase will be recruited in four different countries (Argentina, Brazil, Colombia, and Spain). Patients will be randomized to receive BNZ 150 mg/day for 60 days, 400 mg/day for 15 days, or 300 mg/day for 60 days (comparator arm). The primary outcome is the efficacy of three different BNZ therapeutic schemes in terms of dose and duration. Efficacy will be assessed according to the proportion of patients with sustained parasitic load suppression in peripheral blood measured by polymerase chain reaction. The secondary outcomes are related to pharmacokinetics and drug tolerability. The follow-up will be 12 months from randomization to end of study participation. Recruitment was started in April 2018.Conclusion: This is a clinical trial conducted for the assessment of different dose schemes of BNZ compared with the standard treatment regimen for the treatment of CD in the chronic phase. MULTIBENZ may help to clarify which is the most adequate BNZ regimen in terms of efficacy and safety, predicated on sustained parasitic load suppression in peripheral blood.

Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: A long-term follow up study

“…The BZN beneficial effect was not related to treatment period or daily dose, although this dosage is considered sub-dose by the current guidelines. Few studies addressed different BZN dose regimens, some with drugs association, but all of them used parasite load as a surrogate for efficacy and did not analyze patients’ clinical progression [ 25 , 28 , 29 , 33 ]. Also, changes in post-treatment serological curve occur only after a long-term follow-up.…”

“…Studies performed in the 1990s and 2000s showed that trypanocidal treatment may promote some positive results on parasitemia, serology, and heart disease progression [ 23 , 24 ]. More recently, most clinical trials tested trypanocidal treatment efficacy by means of polymerase chain reaction (PCR) as the main parasitological outcome [25] , [26] , [27] , [28] , [29] . Similarly, observational studies followed the same outcome [ 30 , 31 ].…”

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy

“…The BENEFIT study, the most extensive clinical trial with patients with CCC performed to date, showed that 192 (13.4%) of patients interrupted treatment during the study due to drug adverse events (AEs) ( Morillo et al., 2015 ). Thus, in recent years, new clinical studies are making efforts to find new strategies to decrease Bz dosage and even increase its efficacy ( Almeida et al., 2019 ; Molina-Morant et al., 2020a ; Torrico et al., 2021 ) to reduce the occurrence of adverse events, thus enhancing treatment compliance ( Ciapponi et al., 2020 ). On the other hand, efficacy of Bz treatment in progression of severity of CCC is still on debate ( Rassi et al., 2017 ).…”

Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients

“…Around 70% of patients still had positive lytic antibodies; some presented anti-T.cruzi IgG antibody titers and positive T. cruzi PCR findings (Alarcoń de Noya et al, 2011). Considering that Bnz is highly effective in the acute phase and during childhood in other endemic regions where other parasite DTUs prevail (Bianchi et al, 2015;Moscatelli et al, 2019), these data suggested therapeutic failure and consequently a second treatment was administered to people with persistence of lytic antibodies and/or positive PCR results, however without outcome improvement (Garcia-Bournissen, 2019;Molina-Morant et al, 2020).…”