**3.3 Design of clinical trial programs**

### *3.3.1 Trial methodology considerations*

Despite the long history of clinical research in Chagas disease, the PAHO guidelines emphasize the paucity of high-quality clinical evidence. Clinical trials must be rigorously conducted, tightly controlled scientific experiments in carefully selected patient populations yet sufficiently representative and pragmatic to make the results relevant to real-world clinical practice. This balancing act is not easy to achieve and may be a contributing factor to inconsistency of trial results in Chagas disease. Trial heterogeneity is been a major confounding factor in achieving a consistent and robust conclusion on treatment effects and is evident from several systematic reviews.

A comprehensive analysis of the clinical trials landscape in Chagas disease conducted by Maguire et al. [36] analyzed 109 interventional trials of antitrypanosomal agents conducted from 1997 to 2019. One-fifth of the trials were conducted in nonendemic regions. Just over three quarters of the 23,000 patients in these studies were in active treatment arms and almost one-quarter had no therapy or placebo. Study sample sizes covered a wide range from 6 to 3703 patients with median value of 53 patients, and most studies were conducted in patients with chronic disease. Benznidazole (mainly monotherapy) accounted for 85% of active treatments and NFX for a mere 5.6%, with the remainder being azoles (2%) or unspecified drugs. These authors highlight the enormous heterogeneity of treatment regimens, study designs, and diagnostic methods and advocate a common pooled data platform to facilitate further research.

Studies addressing the impact of antitrypanosomal therapy on progression to cardiac disease were evaluated by Villar et al. [51] in their systematic review of 13 studies. Ten of these 13 studies had BZN arms, 5 included NFX, 4 allopurinol, one itraconazole, and 7 included placebo controls. Significant heterogeneity in study design, response to treatment, and patient outcomes were noted. Overall, no significant treatment effect on cardiac progression was found.

Chadalawada et al. [52] analyzed 32 trials to assess the impact of antitrypanosomal therapy on developing chronic cardiomyopathy in patients with both acute (9 studies) and chronic indeterminate (23 trials) disease. All but three of these trials were prospective cohort studies with notably heterogeneous designs. These authors found a much higher rate of cardiac progression in patients with acute disease (4.6% annually) than those with chronic disease (1.9% per annum). This increase did not appear to be influenced by the route of parasite transmission. Studies conducted in Brazil also had higher rates of cardiomyopathy than other countries. In contrast to Villar et al. this study observed lower rates of cardiomyopathy in trials with antitrypanosomal therapy compared with those without.

Patient availability may be an underlying contributing factor to the diversity of clinical trials noted above and some populations such as acute disease and pediatric patients are challenging to recruit. Identifying patients soon after infection is ideal, but unfortunately, most *Trypanosoma cruzi* infections are asymptomatic and access to diagnostics in rural areas of endemic countries is poor. While national-level screening programs may exist in antenatal/perinatal settings, blood banks, and some hospital settings such as organ transplantation, we are unaware of coordinated systematic population screening across endemic regions, which could support multinational trial participation. Most patients are diagnosed in the stages of chronic indeterminate disease (CID) or having developed chronic determinate disease (CDD) with

## *New Therapeutics for Chagas Disease: Charting a Course to Drug Approval DOI: http://dx.doi.org/10.5772/intechopen.102891*

overt clinical end organ damage. Clinical researchers should pay special attention to optimizing population screening to efficiently use study resources, time, and costs. Widening the availability and use of immunochromatographic rapid diagnostic tests [53] in endemic regions may be a useful and pragmatic approach to improved study subject screening. Furthermore, the increasing trend toward decentralizing studies and use of remote technologies [54] may facilitate participation of patients in more remote regions, especially for screening and follow-up visits.
