Study protocol for controlled human infection for penicillin G againstStreptococcus pyogenes: a double-blinded, placebo-controlled, randomised trial to determine the minimum concentration required to prevent experimental pharyngitis (the CHIPS trial)

Abstract

IntroductionRegular intramuscular benzathine penicillin G injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. As the pharmacological correlate of protection remains unknown, it is difficult to recommend changes to this established regimen. Determining the minimum effective penicillin exposure required to preventStreptococcus pyogenesinfection will accelerate development of new long-acting penicillins for RHD prevention as well as inform opportunities to improve existing regimens. The CHIPS trial will address this knowledge gap by directly testing protection afforded by different steady state plasma concentrations of penicillin in an established model of experimental humanS. pyogenespharyngitis.Methods and analysisThis is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18–40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous penicillin infusions targeting five different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. Each participant’s penicillin pharmacokinetic parameters will be established prior to the challenge, to ensure accurate dosing for the continuous infusion. Following the challenge with a well-characterised strain ofS. pyogenes, participants will be observed for up to 6 days for the development of pharyngitis and treated with antibiotics prior to discharge. The primary objective is to determine the minimum effective steady-state plasma penicillin concentration required to prevent experimental pharyngitis. Secondary objectives will explore systemic and mucosal immunoinflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination and qualitative evaluation of the participant experience.Ethics and disseminationEthical approval has been obtained (Bellberry Human Research Ethics Committee). Findings will be reported in peer-reviewed publications and presented at national/international stakeholder forums.Trial registration numberACTRN12621000751875.

Searching for Strep A in the clinical environment during a human challenge trial: a sub-study protocol

“…This sub-study forms a component of the C ontrolled h uman i nfection for p enicillin against S treptococcus pyogenes (CHIPS) Trial, (registration number ACTRN12621000751875), a double-blind, placebo-controlled, randomized trial using a previously described human challenge model [ 31 ]. Briefly, the CHIPS Trial is designed to determine the optimal dose of penicillin needed to prevent Strep A pharyngitis, conducted in a purpose-built research facility resembling a hospital ward managed by a contract research organization (CRO).…”

“…The CHIPS Trial will be recruiting 60 participants as dictated by sample size calculations [ 31 ]. For this pilot sub-study, a formal sample size calculation has not been performed.…”

“…While verification of many of these transmission mechanisms is still required, it is acknowledged that the type of spread from infected to uninfected individuals may vary according to the clinical manifestation of infection [30]. This protocol, embedded in a human challenge study evaluating the minimum concentration of penicillin required to prevent pharyngitis infection [31], defines the experimental methodology we designed to further understand the transmission potential of Strep A pharyngitis in a controlled setting.…”

“…This protocol, embedded in a human challenge study evaluating the minimum concentration of penicillin required to prevent pharyngitis infection [ 31 ], defines the experimental methodology we designed to further understand the transmission potential of Strep A pharyngitis in a controlled setting.…”