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

Prabin Dahal; Julie Anne Simpson; Salim Abdulla; Jane Achan; Ishag Adam; Aarti Agarwal; Richard Allan; Anupkumar R. Anvikar; Emmanuel Arinaitwe; Elizabeth A. Ashley; Ghulam Rahim Awab; Quique Bassat; Anders Bjorkman; Francois Bompart; Steffen Borrmann; Teun Bousema; Ingrid Broek; Hasifa Bukirwa; Verena I. Carrara; Marco Corsi; Michel Cot; Umberto D'Alessandro; Timothy M. E. Davis; Marit de Wit; Philippe Deloron; Meghna Desai; Pedro Rafael Dimbu; Djibrine Djalle; Abdoulaye Djimde; Grant Dorsey; Ogobara K. Doumbo; Chris J. Drakeley; Stephan Duparc; Michael D. Edstein; Emmanuelle Espie; Abul Faiz; Catherine Falade; Caterina Fanello; Jean-Francois Faucher; Babacar Faye; Filomeno de Jesus Fortes; Nahla B. Gadalla; Oumar Gaye; J. Pedro Gil; Brian Greenwood; Anastasia Grivoyannis; Kamal Hamed; Tran Tinh Hien; David Hughes; Georgina Humphreys; Jimee Hwang; Maman Laminou Ibrahim; Bart Janssens; Vincent Jullien; Elizabeth Juma; Erasmus Kamugisha; Corine Karema; Harin A. Karunajeewa; Jean R. Kiechel; Fred Kironde; Poul-Erik Kofoed; Peter G. Kremsner; Valerie Lameyre; Sue J. Lee; Kevin Marsh; Andreas Martensson; Mayfong Mayxay; Herve Menan; Petra Mens; Theonest K. Mutabingwa; Jean-Louis Ndiaye; Billy E. Ngasala; Harald Noedl; Francois Nosten; Andre Toure Offianan; Mary Oguike; Bernhards R. Ogutu; Piero Olliaro; Jean Bosco Ouedraogo; Patrice Piola; Christopher V. Plowe; Mateusz M. Plucinski; Oliver James Pratt; Zulfikarali Premji; Michael Ramharter; Christophe Rogier; Lars Rombo; Philip J. Rosenthal; Patrick Sawa; Birgit Schramm; Carol Sibley; Veronique Sinou; Sodiomon Sirima; Frank Smithuis; Sarah G. Staedke; Inge Sutanto; Ambrose Otau Talisuna; Joel Tarning; Walter R. J. Taylor; Emmanuel Temu; Kamala L. Thriemer; Nhien Nguyen Thuy; Venkatachalam Udhayakumar; Johan Ursing; Michel van Herp; Michele van Vugt; Christopher Whitty; Yavo William; Cornelis Winnips; Issaka Zongo; Philippe Guerin; Ric N. Price; Kasia Stepniewska; WorldWide Antimalarial Resistance

doi:10.1186/s12936-019-2837-4

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

Prabin Dahal, Julie Anne Simpson, Salim Abdulla, Jane Achan, Ishag Adam, Aarti Agarwal, Richard Allan, Anupkumar R. Anvikar, Emmanuel Arinaitwe, Elizabeth A. Ashley, …

Malaria journal, Vol.18(1), pp.225-225

05/07/2019

DOI: https://doi.org/10.1186/s12936-019-2837-4

PMCID: PMC6612160

PMID: 31277713

Abstract

Infectious Diseases

Life Sciences & Biomedicine

Parasitology

Science & Technology

Tropical Medicine

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.

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Title: Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
Creators - without role: Prabin Dahal - World Wide Antimalarial Resistance Network WWARN, Oxford, England
Julie Anne Simpson - University of Melbourne
Salim Abdulla - Ifakara Hlth Inst, Dar Es Salaam, Tanzania
Jane Achan - Massachusetts Rehabilitation Commission
Ishag Adam - University of Khartoum
Aarti Agarwal - Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA
Richard Allan - Mentor
Anupkumar R. Anvikar - Natl Inst Malaria Res, Sector 8, Dwarka, New Delhi 110077, India
Emmanuel Arinaitwe - Infect Dis Res Collaborat, Kampala, Uganda
Elizabeth A. Ashley - Myanmar Oxford Clin Res Unit, Yangon, Myanmar
Ghulam Rahim Awab - Mahidol University
Quique Bassat - Ctr Investigacao Saude Manhica CISM, Maputo, Mozambique
Anders Bjorkman - Karolinska Institutet
Francois Bompart - Sanofi Access Med, Gentilly, France
Steffen Borrmann - College Station Medical Center
Teun Bousema - Radboud Inst Hlth Sci, Radboudumc Nijmegen, Nijmegen, Netherlands
Ingrid Broek - Centrum Infectieziektebestrijding, Epidemioloog Epidemiol Surveillance RIVM, Bilthoven, Netherlands
Hasifa Bukirwa - African Field Epidemiol Network, Kampala, Uganda
Verena I. Carrara - Shoklo Malaria Research Unit
Marco Corsi - Private Consultancy Drug Dev Trop Dis, Sigma Tau SpA Ind Farmaceutiche Riunite, Pomezia, Rome, Italy
Michel Cot - Université Paris Cité
Umberto D'Alessandro - Massachusetts Rehabilitation Commission
Timothy M. E. Davis - University of Western Australia
Marit de Wit - College Station Medical Center
Philippe Deloron - Université Paris Cité
Meghna Desai - Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA
Pedro Rafael Dimbu - Natl Malaria Control Program, Luanda, Angola
Djibrine Djalle - Inst Pasteur, BP 923, Bangui, Cent Afr Republ
Abdoulaye Djimde - Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali
Grant Dorsey - College Station Medical Center
Ogobara K. Doumbo - College Station Medical Center
Chris J. Drakeley - Supreme Council Of Health
Stephan Duparc - College Station Medical Center
Michael D. Edstein - Australian Army Malaria Inst, Brisbane, Qld, Australia
Emmanuelle Espie - R&D Ctr, GSK Vaccines, Clin & Epidemiol Dept, Epicentre, Ave Fleming 20,1300 Wavre,8 Rue St Sabin, F-75011 Paris, France
Abul Faiz - Malaria Res Grp, Chittagong, Bangladesh
Catherine Falade - University of Ibadan
Caterina Fanello - University of Oxford
Jean-Francois Faucher - College Station Medical Center
Babacar Faye - College Station Medical Center
Filomeno de Jesus Fortes - Natl Malaria Control Program, Luanda, Angola
Nahla B. Gadalla - College Station Medical Center
Oumar Gaye - College Station Medical Center
J. Pedro Gil - Karolinska Institutet
Brian Greenwood - Supreme Council Of Health
Anastasia Grivoyannis - Johns Hopkins University
Kamal Hamed - Basilea Pharmaceut Int Ltd, Basel, Switzerland
Tran Tinh Hien - University of Oxford
David Hughes - Novartis Int AG, Basel, Switzerland
Georgina Humphreys - Wellcome Trust
Jimee Hwang - Centers for New Horizons
Maman Laminou Ibrahim - College Station Medical Center
Bart Janssens - Médecins Sans Frontières
Vincent Jullien - Université Paris Cité
Elizabeth Juma - College Station Medical Center
Erasmus Kamugisha - Weill Bugando Univ Coll Hlth Sci, Mwanza, Tanzania
Corine Karema - Minist Hlth, Natl Malaria Control Program TRAC Plus, Kigali, Rwanda
Harin A. Karunajeewa - College Station Medical Center
Jean R. Kiechel - Drugs Neglected Dis initiat, Geneva, Switzerland
Fred Kironde - Supreme Council Of Health
Poul-Erik Kofoed - Bandim Hlth Project, Indepth Network, Apartado 861, Bissau, Guinea Bissau
Peter G. Kremsner - University of Tübingen
Valerie Lameyre - Sanofi Access Med, Gentilly, France
Sue J. Lee - Mahidol University
Kevin Marsh - University of Oxford
Andreas Martensson - Uppsala University
Mayfong Mayxay - Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit
Herve Menan - Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire
Petra Mens - College Station Medical Center
Theonest K. Mutabingwa - University of Dar es Salaam
Jean-Louis Ndiaye - College Station Medical Center
Billy E. Ngasala - Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania
Harald Noedl - University of Vienna
Francois Nosten - University of Oxford
Andre Toure Offianan - Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire
Mary Oguike - Supreme Council Of Health
Bernhards R. Ogutu - College Station Medical Center
Piero Olliaro - World Bank
Jean Bosco Ouedraogo - Inst Rech Sci Sante, Direct Regionale Ouest, Bobo Dioulasso, Burkina Faso
Patrice Piola - Inst Pasteur Cambodge, Phnom Penh, Cambodia
Christopher V. Plowe - Duke University
Mateusz M. Plucinski - US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, US Presidents Malaria Initiat, Atlanta, GA USA
Oliver James Pratt - Minist Hlth & Social Welf, Natl Malaria Control Program, Monrovia, Liberia
Zulfikarali Premji - Muhimbili Univ Coll Hlth Sci, Dar Es Salaam, Tanzania
Michael Ramharter - Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany
Christophe Rogier - Div Expertise & Def Hlth strategy, Cent Directorate, French Mil Hlth Serv, Paris, France
Lars Rombo - Uppsala University
Philip J. Rosenthal - College Station Medical Center
Patrick Sawa - Human Hlth Div, Int Ctr Insect Physiol & Ecol, Mbita, Kenya
Birgit Schramm - Epicentre, Paris, France
Carol Sibley - WWARN, Oxford, England
Veronique Sinou - Aix-Marseille University
Sodiomon Sirima - GRAS, 06 BP 10248, Ouagadougou 06, Burkina Faso
Frank Smithuis - Myanmar Oxford Clin Res Unit, Oxford, England
Sarah G. Staedke - Supreme Council Of Health
Inge Sutanto - University of Indonesia
Ambrose Otau Talisuna - Birmingham Repertory Theatre
Joel Tarning - WorldWide Antimalarial Resistance Network, Oxford, England
Walter R. J. Taylor - Mahidol University
Emmanuel Temu - Mentor
Kamala L. Thriemer - Charles Darwin University
Nhien Nguyen Thuy - University of Oxford
Venkatachalam Udhayakumar - Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch & Presidents Malaria Initiat, Atlanta, GA USA
Johan Ursing - Karolinska Institutet
Michel van Herp - College Station Medical Center
Michele van Vugt
Christopher Whitty - Supreme Council Of Health
Yavo William - Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire
Cornelis Winnips - NovartisInternat AG, Basel, Switzerland
Issaka Zongo - Inst Rech Sci Sante, Direct Regionale lOuest, Bobo Dioulasso, Burkina Faso
Philippe Guerin - World Wide Antimalarial Resistance Network WWARN, Oxford, England
Ric N. Price - Charles Darwin University
Kasia Stepniewska - World Wide Antimalarial Resistance Network WWARN, Oxford, England
WorldWide Antimalarial Resistance
Publication Details: Malaria journal, Vol.18(1), pp.225-225
Publisher: Springer Nature
Number of pages: 14
Grant note: Nuffield Department of Clinical Medicine, University of Oxford 200909 / Wellcome Trust Bill and Melinda Gates Foundation; Bill & Melinda Gates Foundation ExxonMobil Foundation; Exxon Mobil Corporation 1104975 / Australian National Health and Medical Research Council; National Health and Medical Research Council (NHMRC) of Australia
Identifiers: 9929091108331
Academic Unit: Qassim University
Language: English
Resource Type: Journal article