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Tafenoquine co-administered with dihydroartemisinin–piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study - 28/09/23

Doi : 10.1016/S1473-3099(23)00213-X 
Inge Sutanto, ProfMD a, *, Amin Soebandrio, ProfMD b, *, Lenny L Ekawati, MSc a, c, Krisin Chand, MD a, c, Rintis Noviyanti, PhD b, Ari Winasti Satyagraha, Dr sc hum b, Decy Subekti, PhD a, c, Yulia Widya Santy, MPH a, c, Chelzie Crenna-Darusallam, MBiotech b, d, Instiaty Instiaty, MD a, Waras Budiman, MD e, Catur Bidik Prasetya, MD e, Soroy Lardo, MD e, Iqbal Elyazar, DPhil c, Stephan Duparc, MD f, Eve Cedar, MSc g, Katie Rolfe, MSc g, Disala Fernando, MD g, Alessandro Berni, MSc g, Siôn Jones, PhD g, Jörg-Peter Kleim, PhD g, Kim Fletcher, BA g, Hema Sharma, FRCPath g, Ana Martin, PhD g, Maxine Taylor, BSc h, Navin Goyal, PhD i, Justin A Green, MD g, Lionel K Tan, FRCP g, , , J Kevin Baird, ProfPhD a, c, j,
a Faculty of Medicine, University of Indonesia, Jakarta, Indonesia 
b Eijkman Institute for Molecular Biology, Jakarta, Indonesia 
c University of Oxford Clinical Research Unit—Indonesia, Jakarta, Indonesia 
d Mochtar Riady Institute for Nanotechnology, Banten, Indonesia 
e Health Service, Army of the Republic of Indonesia, Jakarta, Indonesia 
f Medicines for Malaria Venture, Geneva, Switzerland 
g GSK, Brentford, UK 
h GSK, Ware, UK 
i GSK, Collegeville, PA, USA 
j Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 

* Correspondence to: Dr Lionel Tan, Global Health Research and Development, GSK, Brentford, Middlesex TW8 9GS, UK Global Health Research and Development GSK Brentford Middlesex TW8 9GS UK

Summary

Background

Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin–piperaquine for the radical cure of P vivax malaria.

Methods

In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin–piperaquine alone, dihydroartemisinin–piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin–piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed.

Findings

Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4–22) in patients treated with dihydroartemisinin–piperaquine alone versus 21% (11–34) in patients treated with tafenoquine plus dihydroartemisinin–piperaquine (hazard ratio 0·44; 95% CI [0·29–0·69]) and 52% (37–65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin–piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin–piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin–piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively.

Interpretation

Although tafenoquine plus dihydroartemisinin–piperaquine was statistically superior to dihydroartemisinin–piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria.

Funding

ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK.

Translation

For the Indonesian translation of the abstract see Supplementary Materials section.

Le texte complet de cet article est disponible en PDF.

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© 2023  The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 23 - N° 10

P. 1153-1163 - octobre 2023 Retour au numéro
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