Phase 2 pilot trial to optimise pharmacometric evaluations in Chagas disease (CHARM: CHAgas disease PharMacometrics)

Abstract

Chagas disease is a neglected disease caused by Trypanosoma cruzi that currently affects about 7 million people in the Americas and the American diaspora. Only two drugs are available to treat Chagas disease, both are associated with a high incidence of adverse events, particularly in adults, and they are also complex to administer. New treatments are needed urgently, but there is no established method of evaluating new drugs. We describe the study protocol for a pilot phase 2 descriptive observational study of parasite dynamics within the host, followed by a randomised evaluation of the pharmacokinetic-pharmacodynamic properties of subcurative doses of anti-chagasic drugs in patients with chronic Chagas disease. This study is divided into three stages. The general objective of the study is to characterise the dynamics of the parasite within the host at steady state and the pharmacokinetic-pharmacodynamic relationships for each of the three drugs studied. This is based on characterising the structure and parameters of a pharmacodynamic model of parasite turnover within the host. Each stage of the study targets specific key parameters in the pharmacodynamic model of parasite dynamics (both the blood stage and the tissue stage) for individual research participants. The primary outcome measure for all three stages is blood-stage parasite density, measured by quantitative PCR. Upon completion, research participants will receive definitive treatment for Chagas disease in accordance with national guidelines. Registration ISRCTN (ISRCTN26467068; 01/07/2021).