Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

Background: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. Methods and findings: We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. Conclusions: These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance. Using a novel modelling approach, Mousa and colleagues investigate the design and analysis of malaria chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. Author summary: Why was this study done?: In 2022, the World Health Organisation (WHO) released updated guidelines for the implementation of malaria chemoprevention and guidance for undertaking chemoprevention efficacy studies. We sought to understand how study design and trial setting characteristics influence the ability to assess chemoprevention efficacy and duration of drug protection. The impact of drug resistance on chemoprevention is not well understood, and there is a need for a method that produces measures of drug resistance effects, which can be applied to different settings. What did the researchers do and find?: We fitted a Bayesian Markov Chain Monte Carlo (MCMC) to simulated trial data for a number of trial designs and scenarios. We find that the WHO recommendation of 28 days of follow-up is insufficient to precisely estimate duration of drug protection or protective efficacy. In seasonal settings, in the absence of a control arm, it is impossible to distinguish between changing transmission and waning drug protection when estimating protective efficacy. What do these findings mean?: Where feasible, particularly in settings of seasonal transmission and/or trials without a control arm, extending follow-up to 42 or 63 days can substantially improve the ability to accurately estimate chemoprevention outcomes. Although long follow-up can improve precision and power, decisions on study design should also consider costs and trial feasibility. [ABSTRACT FROM AUTHOR]