Short-course Benznidazole Treatment to Reduce Trypanosoma cruzi Parasitic Load in Women of Reproductive Age (BETTY): A Non-inferiority Randomized Controlled Trial Study Protocol
Authors: Cafferata María Luisa , Toscani María Ayelen , Klein Karen , Althabe Fernando , Bergel Eduardo , Berrueta Mabel , Ciganda Álvaro , Danesi Emmaria , Dumonteil Eric , Gibbons Luz , Gulayin Pablo E. , Herrera Claudia , Shaffer Jeffrey G. , Schijman Alejandro G. , Estani Sergio Sosa , Stella Candela , Buekens Pierre 
Published: June 2020

Abstract
BackgroundRetrospective observational studies suggest that transmission of the Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The BENEFIT trial, conducted in Argentina, compared a BZN 60-day/300 mg per day (60d/300mg) course (for subjects weighing 60kg) vs. placebo among patients with Chagas’ cardiomyopathy. The rate of conversion to negative conventional PCR (PCR) in the blood was 66.2% in the BZN group vs. 33.5% in the placebo group. Of concern, the rate of treatment interruption caused by adverse events was 23.9% in the BZN group.The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300mg course is not yet established. Observational, animal, and pharmacokinetics (PK) studies suggest that the 60d/300mg course may be overdosing patients unnecessarily and increasing adverse events. Young and healthy subjects might have lower rates of treatment failures and adverse events. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed.Methods and designWe are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150mg/day (30d/150mg) vs. BZN 60d/300mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at six months postpartum, and follow them up with the following specific aims:Specific Aim 1: to measure the effect of BZN 30d/150mg compared to 60d/300mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately (Specific Aim 1a) and 10 months (Specific Aim 1b) after treatment.Hypothesis 1a: the frequency of positive PCR and the parasitic load measured by qPCR immediately after BZN 30d/150mg will be non-inferior (Non-Inferiority (NI) margin for PCR: 10% absolute difference) to BZN 60d/300mg.Hypothesis 1b: the frequency of positive PCR and the parasitic load measured by qPCR 10 months after BZN 30d/150mg will be non-inferior (NI margin for PCR: 9% absolute difference) to BZN 60d/300mg.Specific Aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption of BZN 30d/150mg compared to 60d/300mg.Hypothesis 2: the frequency of serious adverse events and/or any adverse event leading to treatment interruption will be 50% lower with BZN 30d/150mg than with BZN 60d/300mg.Trial registration: ClinicalTrials.gov. Identifier: NCT03672487. Registed 14 September 2018, https://clinicaltrials.gov/ct2/show/NCT03672487?recrs=a&cond=Chagas+Disease&cntry=AR&draw=2&rank=3