Results
REGRESSION, DRUG-INDUCED LIVER INJURY, ADVERSE EVENT, ADVERSE EVENTS
Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned to masked study treatment; 50 per treatment group (battalion 1 n=69; battalion 2 n=81; Trial profileALT=alanine aminotransferase. DP=dihydroartemisinin–piperaquine. mITT=microbiological intention-to-treat. PP=per-protocol. PQ=primaquine. *Participants can be excluded for more than one reason. †The patient discontinued treatment, but continued and completed the study. The safety population included all patients who were randomly assigned and received at least one dose of masked study medication. The mITT population was a subgroup of the safety population who had microscopically confirmed Baseline characteristics for safety populationData are mean (SD), n (%), and median (range). IU=international units.Glucose-6-phosphate dehydrogenase activity ≥5·1 IU/gHb was considered normal based on ≥70% of the site median 7·29 (range 5·77–11·92) IU/gHb established from the first 33 recruited patients who were G6PD normal by the fluorescent spot test.There were no discordant G6PD results between the qualitative fluorescent spot test and the quantitative spectrophotometric assay in any randomly assigned patient.Poor activity score 0; intermediate=activity score=0·25 to 1; normal activity score=1·25–2·25; ultra activity score >2·25 (see In the microbiological intention-to-treat population, 44 patients (88%) in the dihydroartemisinin–piperaquine alone group, 39 patients (78%) in the tafenoquine plus dihydroartemisinin–piperaquine group and 24 patients (48%) in the primaquine plus dihydroartemisinin–piperaquine group had microscopically confirmed Kaplan-Meier survival curves for 6-month relapse-free efficacy for the microbiological intention-to-treat populationDP=dihydroartemisinin–piperaquine. PQ=primaquine. TQ=tafenoquine. *Estimated from Cox's proportional-hazards analysis adjusting for battalion. A hazard ratio of <1 indicates a lower chance of relapse compared with the reference treatment. No patients met the criteria for censoring.Logistic regression analysis of relapse-free efficacy at 6 months (modified intention to treat population)Data are n (%) unless stated otherwise. DP=dihydroartemisinin-piperaquine. Model includes terms for battalion and treatment. Patients who did not show initial clearance of An odds ratio <1 represents a smaller chance of relapse compared with DP alone.An odds ratio <1 represents a smaller chance of relapse compared with primaquine plus DP.Primaquine plus dihydroartemisinin–piperaquine reduced the risk of relapse over 6 months by 74·2% versus dihydroartemisinin–piperaquine alone (HR 0·26; 95% CI 0·16–0·43; The percentage of relapse-free patients in all treatment groups over 6 months was higher in battalion 1 than battalion 2 (battalion 1 dihydroartemisinin–piperaquine alone five [22%] of 23; tafenoquine plus dihydroartemisinin–piperaquine seven [32%] of 22; primaquine plus dihydroartemisinin–piperaquine 19 [79%] of 24; battalion 2 dihydroartemisinin–piperaquine alone one [4%] of 27; tafenoquine plus dihydroartemisinin–piperaquine four [14%] of 28; primaquine plus dihydroartemisinin–piperaquine seven [27%] of 26). The reduction in the 6-month relapse risk for tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin–piperaquine alone was greater for battalion 2 (battalion 1 HR 0·70; 95% CI 0·35–1·39; battalion 2: HR 0·38; 0·21–0·67; see Relapse-free efficacy trends over 4 months were similar to the 6-month results (Treatment groups were well matched for CYP2D6 metaboliser class with 67 (45%) of 150 being categorised as poor or intermediate metabolisers (categorised post-hoc according to Clinical Pharmacogenetics Implementation Consortium guidelines). Logistic regression analyses showed no significant effect of CYP2D6 activity score (Overall, 88 (83%) of 106 of all first relapses were genetically heterologous by microsatellite genotyping and the proportion of heterologous to homologous relapses was not influenced by treatment (The adverse event profile was similar across treatment groups, although the proportion of patients in the primaquine plus dihydroartemisinin–piperaquine group reporting any adverse event was lower than for other groups (Most frequent adverse events and serious adverse events during the double-blind treatment phase (safety population)Data are n (%). DP=dihydroartemisinin–piperaquine.Only adverse events with an onset up to day 29 are presented. The interpretation of the incidence of adverse events after day 29 is likely to be confounded by medication administered to treat relapses (primaquine plus DP).One patient was diagnosed with grade 1 drug-induced liver injury at the time of their first Five serious adverse events were reported during the 6-month follow-up of which two were considered possibly related to treatment by the investigator (A higher percentage of patients in the tafenoquine plus dihydroartemisinin–piperaquine group (12 [24%] of 50) had a clinically significant QTcF prolongation (defined as ≥60 msec change from baseline) on the 12-lead electrocardiogram (dihydroartemisinin–piperaquine alone group seven [14%] of 50; primaquine plus dihydroartemisinin–piperaquine group five [10%] of 50). In all cases, QTcF prolongation was asymptomatic and returned to normal within 1 week without intervention (Haemoglobin values were similar between treatment groups (Box plot of haemoglobin and methaemoglobin values over time (safety population)DP=dihydroartemisinin-piperaquine. PQ=primaquine. RLP=relapse visit. TQ=tafenoquine.Owing to various logistical factors including the global response to the COVID-19 pandemic, it has not, to date, been possible to transport samples for pharmacokinetic analyses to a validated laboratory outside of Indonesia. Pharmacokinetic data from study patients cannot therefore be included in this publication.