*3.4.1 Parasitological, serological, and clinical endpoints*

Sustained decrease in parasitemia and resolution of clinical effects would be appropriate clinical trial endpoints for efficacy in patients with acute Chagas disease. Well-established microscopy-based methods exist to directly observe detection of circulating parasites; however, these methods lack the exquisite sensitivity and quantitative advantages of PCR for monitoring treatment effect [64]. Use of standardized PCR and serology assays using central laboratories is advisable during phase II and III trials to ensure consistency and comparability. Detailed time course profiles of quantitative changes in parasitemia from presentation to resolution (with and without treatment) are not available in the literature and would need to be generated *de novo.*

While a parasitological response alone may be sufficient to determine drug activity from a mechanistic viewpoint, clinically meaningful trial endpoints that reflect how a patient feels, functions, or survives are essential. Elegant and detailed descriptions of the clinical course of acute disease can be found in the literature [34, 35, 65, 66] but lack the granularity required to develop a robust clinical endpoint for regulatory purposes. If needed, additional data that enhance understanding of clinical parameters in acute disease may be sought through patient chart review (preferably from recent datasets) or by prospective collection, in parallel to, or as part of a Proofof-Concept trial.

As, patients with CID are asymptomatic and parasitemia is often absent or of low-grade intermittent nature, most phase II studies have employed PCR testing and serological tests as to quantitate drug effects. Long-term seroreversion of *T. cruzi* specific IgG, measured by serial assays, is the mostly widely accepted evidence of cure and reflects both parasite and host response [67, 68]. PCR is considered a sensitive

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

tool to assess peripheral parasite load for diagnosis and relapse [69] and is useful as a short-term endpoint for antiparasitic drug effect and dose finding in clinical trials [70]. Nonconventional serological tests with antibodies against specific Chagas*'* antigens [71] may show earlier time course changes and some (e.g., F29- ELISA, AT-ELISA) have been included in regulatory submissions for benznidazole and nifurtimox [72–74].

Some specific challenges associated with choosing cardiac related endpoints have been discussed above in Section 3.1.2 and 3.1.3 will not be repeated. Trials using cardiovascular event endpoints must also be designed to adjust for the other competing risk factors that may confound interpretation of the results [75]. Based on available evidence, the probability to detect meaningful changes in clinical cardiac parameters in studies with BZN monotherapy is extremely low. Finding new biomarkers or imaging tools that may correlate with clinical outcomes or predict for risk of later end-organ damage would significantly accelerate the development of new drugs.

The efficiency of clinical trials in Chagas disease could also be improved if study populations could be enriched by patients most likely to develop progression. Currently, no such early predictive markers of long-term seroreversion or cure exist although many markers of disease progression are under exploration. The ideal characteristic for biomarkers along with a summary of numerous parasitic, molecular, cellular, and host biomarkers studied to date has been reviewed by Pinazo et al. [67].

### *3.4.2 Quality-of-life (QoL) measures*

Most drug studies in Chagas disease have reported adverse events or clinical effects as patient-related outcomes [36]. Quality-of-life (QoL) research using different validated tools has mainly been studied in patients with cardiac disease [76, 77]. In CID patients, QoL measures observed during treatment may be a worthwhile consideration when comparing tolerability or convenience of two active treatments. Regulatory authorities have an active interest in how patient feels and functions, and the United States Food and Drug administration (US FDA) held a patient workshop for Chagas disease that highlighted emotional, financial, and other pragmatic concerns associated with the disease [78]. Where it is appropriate to measure QoL during new therapeutic interventions, carefully constructed patient measures are useful supplements to conventional safety and efficacy parameters.
