Efficacy and safety of alternative benznidazole and nifurtimox regimens for adults with chronic Trypanosoma cruzi infection (TESEO): an open-label, randomised, non-inferiority phase 2b trial.

BACKGROUND: Trypanosoma cruzi infection affects over seven million people worldwide. Standard-of-care benznidazole or nifurtimox causes drug-related adverse events leading to definitive treatment interruption. We evaluated whether shortened, extended, or halved-dose regimens preserve efficacy and improve tolerability. METHODS: TESEO was an open-label, randomised, non-inferiority, phase 2b trial done at outpatient units at three sites in Bolivia: the Cochabamba, Tarija, and Sucre units of the Platform of Comprehensive Care for Patients with Chagas Disease. We included adults (aged 18-50 years, 40-90 kg) with serologically and quantitative PCR (qPCR)-confirmed chronic T cruzi infection in the indeterminate or early cardiac form. Participants were randomly assigned (1:1:1:1:1:1) to benznidazole 150 mg twice daily for 60 days (standard of care), benznidazole 150 mg once daily for 30 days, benznidazole 150 mg once daily for 90 days, nifurtimox 240 mg twice daily for 60 days (standard of care), nifurtimox 240 mg twice daily for 30 days, or nifurtimox 240 mg once daily for 90 days (75 participants per group, with both drugs given orally). Randomisation was computer-generated, using permuted blocks of six stratified by study site. Allocation was concealed by use of sealed envelopes. The primary efficacy outcome was sustained parasitological clearance (all-negative qPCRs for at least four of seven timepoints, 4-36 months) in a modified intention-to-treat (mITT) population of all randomly assigned participants with at least four follow-up qPCR results between 4 and 36 months, including the 36-month follow-up visit; the primary safety outcome was the proportion of patients who received at least one dose of study drug and had at least one drug-related adverse event. Non-inferiority versus the within-drug standard of care was prespecified at a -9·5 percentage-point margin on the risk difference, assessed by a longitudinal generalised estimating (GEE) equation with Bonferroni-adjusted 97·5% CIs. The trial is registered with ClinicalTrials.gov (NCT03981523) and is complete. FINDINGS: Between Dec 18, 2019, and May 20, 2021, 890 individuals were screened and 450 participants were enrolled and randomly assigned. Of 435 participants included in the mITT population, sustained parasitological clearance up to 36 months was seen in 69 (95%) of 73 participants in the benznidazole 60-day group (standard of care), 68 (94%) of 72 in the benznidazole 30-day group, 69 (92%) of 75 in the benznidazole 90-day group, 58 (81%) of 72 in the nifurtimox 60-day group (standard of care), 63 (89%) of 71 in the nifurtimox 30-day group, and 65 (90%) of 72 in the nifurtimox 90-day group. The prespecified primary longitudinal GEE analysis supported non-inferiority for all four experimental groups versus their respective standard of care in the mITT population: benznidazole 30-day group (risk difference experimental minus standard of care -2·0 [97·5% CI -5·41 to 1·45]), benznidazole 90-day group (-2·0 [-5·45 to 1·49]), nifurtimox 30-day group (3·3 [-3·84 to 10·48]), and nifurtimox 90-day group (1·5 [-6·76 to 9·70]); per-protocol estimates were concordant. Overall, 273 (61%) of 449 participants in the safety analysis had at least one drug-related adverse event. Fewer participants in the benznidazole 30-day group had drug-related adverse events (28 [37%] of 75) than in the benznidazole 60-day standard of care group (45 [60%] of 75; risk difference -23 percentage points [95% CI -38 to -7]; adjusted p=0·022); no other comparison was significant. Most drug-related adverse events arose within 10-14 days regardless of treatment duration. INTERPRETATION: Benznidazole 150 mg once daily for 30 days showed non-inferior efficacy and the lowest rate of drug-related adverse events among the regimens tested, supporting its adoption as the preferred benznidazole regimen for chronic Chagas disease; phase 3 trials of long-term efficacy across parasite genotypes and settings are required to support its incorporation into treatment guidelines. The early, duration-independent onset of drug-related adverse events suggests idiosyncratic rather than cumulative toxicity, informing monitoring and regimen design. FUNDING: US National Institutes of Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.