# name
Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis

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WorldWide Antimalarial Resistance Network Methodology Study Group

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Background: Therapeutic efcacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new
infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of
subsequent recrudescence of persistent, sub-microscopic primary infections.
Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan–Meier (K–M)
method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence
Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing
risk event. The complement of the estimate derived using the K–M method (1 minus K–M), and the CIF were used to
derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide
Antimalarial Resistance Network data repository. Absolute diferences in the failure estimates derived using these two
methods were quantifed. In comparative studies, the equality of two K–M curves was assessed using the log-rank
test, and the equality of CIFs using Gray’s k-sample test (both at 5% level of signifcance). Two diferent regression
modelling strategies for recrudescence were considered: cause-specifc Cox model and Fine and Gray’s sub-distributional hazard model.
Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and
2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence
by using 1 minus K–M approach was 0.04% (interquartile range (IQR): 0.00–0.27%, Range: 0.00–3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson’s correlation coefcient
(ρ): 0.38, 95% Confdence Interval (CI) 0.30–0.46] or new infection [ρ: 0.43; 95% CI 0.35–0.54]. In three study arms, the
point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K–M
method was used, but remained below 10% when using the CIF approach, but the 95% confdence interval included
this threshold.
Conclusions: The 1 minus K–M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efcacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials,
particularly in high transmission settings.

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Articles publicats en revistes (ISGlobal)

# metadata.dc.title[].value
Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis