TY - JOUR
T1 - Tafenoquine co-administered with dihydroartemisinin–piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR)
T2 - a randomised, placebo-controlled, efficacy and safety study
AU - Sutanto, Inge
AU - Soebandrio, Amin
AU - Ekawati, Lenny L.
AU - Chand, Krisin
AU - Noviyanti, Rintis
AU - Satyagraha, Ari Winasti
AU - Subekti, Decy
AU - Santy, Yulia Widya
AU - Crenna-Darusallam, Chelzie
AU - Instiaty, Instiaty
AU - Budiman, Waras
AU - Prasetya, Catur Bidik
AU - Lardo, Soroy
AU - Elyazar, Iqbal
AU - Duparc, Stephan
AU - Cedar, Eve
AU - Rolfe, Katie
AU - Fernando, Disala
AU - Berni, Alessandro
AU - Jones, Siôn
AU - Kleim, Jörg Peter
AU - Fletcher, Kim
AU - Sharma, Hema
AU - Martin, Ana
AU - Taylor, Maxine
AU - Goyal, Navin
AU - Green, Justin A.
AU - Tan, Lionel K.
AU - Baird, J. Kevin
N1 - Funding Information:
IS was the principal investigator and JKB was responsible for study conceptualisation. JKB, IS, AS, LLE, RN, AWS, WB, SL, IE, JAG, J-PK, SD, EC, SJ, MT, and NG contributed to the study design and protocol development. SD and LKT were responsible for funding acquisition. LKT, SD, HS, AM, and EC were responsible for the project administration. IS, JKB, AS, KC, LLE, YWS, DS, AWS, WB, CBP, SL, EC, KF, AB, DF, SD, JAG, and LKT contributed to the implementation of the study or data collection. DS, AWS, RN, and CC-D were responsible for laboratory analyses. KR was responsible for statistical analysis. HS and AM led discussion related to the pharmacokinetic data analysis, absence of pharmacokinetic samples and effect on the manuscript, regulatory study activities, and reporting. II, MT, and NG were responsible for the pharmacokinetic data acquisition. HS and AM were responsible for the pharmacokinetic data management activities. JKB, IS, LLE, RN, AWS, LKT, J-PK, DF, SJ, EC, KR, NG, HS, AM, MT, and SD contributed to data interpretation. EC and LKT wrote the first draft of the manuscript and suggested the visual presentation of the data. LKT, JKB, and EC had full access to all the analysed data received to date and verified all data. All authors had access to the available analysed data, contributed to manuscript revision, take responsibility for the content of the manuscript, and had final responsibility for the decision to submit for publication.
Funding Information:
The trial was designed and funded by MMV and supported by the sponsor GSK. The protocol was drafted by GSK with input from MMV and the Indonesian study team. MMV was funded by various donors for this trial including ExxonMobil and it was supported in part by the Gates Foundation (grant number INV-007155/19-BMGF-006), Newcrest Mining, and the UK Department for International Development. GSK funded the costs associated with the development of the present publication. Editorial support after initial draft was provided by Allyson Lehrman and Sarah Hummasti of AOIC (revising the document based on author input, assembling drafts, tables and figures, collating co-author comments, and researching references) and AOIC assisted with graphics; both were funded by the study sponsor, GSK. We express sincere gratitude to the soldiers, officers, and commanders of the Army of the Republic of Indonesia for their support and participation in this clinical trial. We are grateful to all members of the clinical research team at the Eijkman-Oxford Clinical Research Unit, the Eijkman Institute of Molecular Biology, the Faculty of Medicine, University of Indonesia, as well as the Alert Asia Foundation (all in Jakarta). We also thank the entire GSK study team for their contributions to this study.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023
Y1 - 2023
N2 - 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: Medicines for Malaria Venture and GSK. Translation: For the Indonesian translation of the abstract see Supplementary Materials section.
AB - 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: Medicines for Malaria Venture and GSK. Translation: For the Indonesian translation of the abstract see Supplementary Materials section.
UR - http://www.scopus.com/inward/record.url?scp=85164834733&partnerID=8YFLogxK
U2 - 10.1016/S1473-3099(23)00213-X
DO - 10.1016/S1473-3099(23)00213-X
M3 - Article
C2 - 37236221
AN - SCOPUS:85164834733
SN - 1473-3099
VL - 23
SP - 1153
EP - 1163
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 10
ER -