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

WorldWide Antimalarial Resistance

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Abstract

BackgroundTherapeutic efficacy 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.MethodsAntimalarial 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 differences in the failure estimates derived using these two methods were quantified. 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 significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.ResultsData 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 coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 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% confidence interval included this threshold.ConclusionsThe 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy 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.

Original languageEnglish
Article number225
Number of pages14
JournalMalaria Journal
Volume18
DOIs
Publication statusPublished - 5 Jul 2019

Cite this

@article{e32aa41ba48a4a52a4c9e5e917f75110,
title = "Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis",
abstract = "BackgroundTherapeutic efficacy 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.MethodsAntimalarial 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 differences in the failure estimates derived using these two methods were quantified. 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 significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.ResultsData 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 coefficient (rho): 0.38, 95{\%} Confidence Interval (CI) 0.30-0.46] or new infection [rho: 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{\%} confidence interval included this threshold.ConclusionsThe 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy 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.",
keywords = "Plasmodium falciparum, Treatment efficacy study, Competing risk event, DIHYDROARTEMISININ-PIPERAQUINE, FAILURE PROBABILITIES, CUMULATIVE INCIDENCE, RECRUDESCENCE, COMBINATIONS, REINFECTION, CHILDREN, EFFICACY, HAZARDS, MODELS",
author = "{WorldWide Antimalarial Resistance} and Prabin Dahal and Simpson, {Julie Anne} and Salim Abdulla and Jane Achan and Ishag Adam and Aarti Agarwal and Richard Allan and Anvikar, {Anupkumar R.} and Emmanuel Arinaitwe and Ashley, {Elizabeth A.} and Awab, {Ghulam Rahim} and Quique Bassat and Anders Bjorkman and Francois Bompart and Steffen Borrmann and Teun Bousema and Ingrid Broek and Hasifa Bukirwa and Carrara, {Verena I.} and Marco Corsi and Michel Cot and Umberto D'Alessandro and Davis, {Timothy M. E.} and {de Wit}, Marit and Philippe Deloron and Meghna Desai and Dimbu, {Pedro Rafael} and Djibrine Djalle and Abdoulaye Djimde and Grant Dorsey and Doumbo, {Ogobara K.} and Drakeley, {Chris J.} and Stephan Duparc and Edstein, {Michael D.} and Emmanuelle Espie and Abul Faiz and Catherine Falade and Caterina Fanello and Jean-Francois Faucher and Babacar Faye and Fortes, {Filomeno de Jesus} and Gadalla, {Nahla B.} and Oumar Gaye and Gil, {J. Pedro} and Brian Greenwood and Anastasia Grivoyannis and Kamal Hamed and Hien, {Tran Tinh} and David Hughes and Georgina Humphreys and Jimee Hwang and Ibrahim, {Maman Laminou} and Bart Janssens and Vincent Jullien and Elizabeth Juma and Erasmus Kamugisha and Corine Karema and Karunajeewa, {Harin A.} and Kiechel, {Jean R.} and Fred Kironde and Poul-Erik Kofoed and Kremsner, {Peter G.} and Valerie Lameyre and Lee, {Sue J.} and Kevin Marsh and Andreas Martensson and Mayfong Mayxay and Herve Menan and Petra Mens and Mutabingwa, {Theonest K.} and Jean-Louis Ndiaye and Ngasala, {Billy E.} and Harald Noedl and Francois Nosten and Offianan, {Andre Toure} and Mary Oguike and Ogutu, {Bernhards R.} and Piero Olliaro and Ouedraogo, {Jean Bosco} and Patrice Piola and Plowe, {Christopher V.} and Plucinski, {Mateusz M.} and Pratt, {Oliver James} and Zulfikarali Premji and Michael Ramharter and Christophe Rogier and Lars Rombo and Rosenthal, {Philip J.} and Patrick Sawa and Birgit Schramm and Carol Sibley and Veronique Sinou and Sodiomon Sirima and Frank Smithuis and Staedke, {Sarah G.} and Inge Sutanto and Talisuna, {Ambrose Otau} and Joel Tarning and Taylor, {Walter R. J.} and Emmanuel Temu and Thriemer, {Kamala L.} and Thuy, {Nhien Nguyen} and Venkatachalam Udhayakumar and Johan Ursing and {van Herp}, Michel and {van Vugt}, Michele and Christopher Whitty and Yavo William and Cornelis Winnips and Issaka Zongo and Philippe Guerin and Price, {Ric N.} and Kasia Stepniewska",
year = "2019",
month = "7",
day = "5",
doi = "10.1186/s12936-019-2837-4",
language = "English",
volume = "18",
journal = "Malaria Journal",
issn = "1475-2875",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria

T2 - a WorldWide Antimalarial Resistance Network individual participant data meta-analysis

AU - WorldWide Antimalarial Resistance

AU - Dahal, Prabin

AU - Simpson, Julie Anne

AU - Abdulla, Salim

AU - Achan, Jane

AU - Adam, Ishag

AU - Agarwal, Aarti

AU - Allan, Richard

AU - Anvikar, Anupkumar R.

AU - Arinaitwe, Emmanuel

AU - Ashley, Elizabeth A.

AU - Awab, Ghulam Rahim

AU - Bassat, Quique

AU - Bjorkman, Anders

AU - Bompart, Francois

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Broek, Ingrid

AU - Bukirwa, Hasifa

AU - Carrara, Verena I.

AU - Corsi, Marco

AU - Cot, Michel

AU - D'Alessandro, Umberto

AU - Davis, Timothy M. E.

AU - de Wit, Marit

AU - Deloron, Philippe

AU - Desai, Meghna

AU - Dimbu, Pedro Rafael

AU - Djalle, Djibrine

AU - Djimde, Abdoulaye

AU - Dorsey, Grant

AU - Doumbo, Ogobara K.

AU - Drakeley, Chris J.

AU - Duparc, Stephan

AU - Edstein, Michael D.

AU - Espie, Emmanuelle

AU - Faiz, Abul

AU - Falade, Catherine

AU - Fanello, Caterina

AU - Faucher, Jean-Francois

AU - Faye, Babacar

AU - Fortes, Filomeno de Jesus

AU - Gadalla, Nahla B.

AU - Gaye, Oumar

AU - Gil, J. Pedro

AU - Greenwood, Brian

AU - Grivoyannis, Anastasia

AU - Hamed, Kamal

AU - Hien, Tran Tinh

AU - Hughes, David

AU - Humphreys, Georgina

AU - Hwang, Jimee

AU - Ibrahim, Maman Laminou

AU - Janssens, Bart

AU - Jullien, Vincent

AU - Juma, Elizabeth

AU - Kamugisha, Erasmus

AU - Karema, Corine

AU - Karunajeewa, Harin A.

AU - Kiechel, Jean R.

AU - Kironde, Fred

AU - Kofoed, Poul-Erik

AU - Kremsner, Peter G.

AU - Lameyre, Valerie

AU - Lee, Sue J.

AU - Marsh, Kevin

AU - Martensson, Andreas

AU - Mayxay, Mayfong

AU - Menan, Herve

AU - Mens, Petra

AU - Mutabingwa, Theonest K.

AU - Ndiaye, Jean-Louis

AU - Ngasala, Billy E.

AU - Noedl, Harald

AU - Nosten, Francois

AU - Offianan, Andre Toure

AU - Oguike, Mary

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero

AU - Ouedraogo, Jean Bosco

AU - Piola, Patrice

AU - Plowe, Christopher V.

AU - Plucinski, Mateusz M.

AU - Pratt, Oliver James

AU - Premji, Zulfikarali

AU - Ramharter, Michael

AU - Rogier, Christophe

AU - Rombo, Lars

AU - Rosenthal, Philip J.

AU - Sawa, Patrick

AU - Schramm, Birgit

AU - Sibley, Carol

AU - Sinou, Veronique

AU - Sirima, Sodiomon

AU - Smithuis, Frank

AU - Staedke, Sarah G.

AU - Sutanto, Inge

AU - Talisuna, Ambrose Otau

AU - Tarning, Joel

AU - Taylor, Walter R. J.

AU - Temu, Emmanuel

AU - Thriemer, Kamala L.

AU - Thuy, Nhien Nguyen

AU - Udhayakumar, Venkatachalam

AU - Ursing, Johan

AU - van Herp, Michel

AU - van Vugt, Michele

AU - Whitty, Christopher

AU - William, Yavo

AU - Winnips, Cornelis

AU - Zongo, Issaka

AU - Guerin, Philippe

AU - Price, Ric N.

AU - Stepniewska, Kasia

PY - 2019/7/5

Y1 - 2019/7/5

N2 - BackgroundTherapeutic efficacy 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.MethodsAntimalarial 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 differences in the failure estimates derived using these two methods were quantified. 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 significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.ResultsData 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 coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 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% confidence interval included this threshold.ConclusionsThe 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy 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.

AB - BackgroundTherapeutic efficacy 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.MethodsAntimalarial 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 differences in the failure estimates derived using these two methods were quantified. 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 significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.ResultsData 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 coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 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% confidence interval included this threshold.ConclusionsThe 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy 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.

KW - Plasmodium falciparum

KW - Treatment efficacy study

KW - Competing risk event

KW - DIHYDROARTEMISININ-PIPERAQUINE

KW - FAILURE PROBABILITIES

KW - CUMULATIVE INCIDENCE

KW - RECRUDESCENCE

KW - COMBINATIONS

KW - REINFECTION

KW - CHILDREN

KW - EFFICACY

KW - HAZARDS

KW - MODELS

U2 - 10.1186/s12936-019-2837-4

DO - 10.1186/s12936-019-2837-4

M3 - Article

VL - 18

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

M1 - 225

ER -