Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low dose primaquine or placebo

Background: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. Methods: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months–11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. Results: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). Conclusions: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial

Background WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. Methods We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A− variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether–lumefantrine or dihydroartemisinin–piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. Findings Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether–lumefantrine plus single low-dose primaquine group, 286 to the artemether–lumefantrine plus placebo group, 283 to the dihydroartemisinin–piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin–piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study—these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference −0·66%, 95% CI −1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (−0·014%, −0·68 to 0·65; p=0·97). Interpretation Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. Funding UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa

When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available.(www.clinicalTrials.gov : NCT02492178

A randomised, double-blind, placebo-controlled, non-inferiority trial to assess the safety of age-dosed single low dose primaquine in falciparum-infected African children with G6PD deficiency

Background: The WHO recommends gametocytocidal, single low dose primaquine (SLDPQ) for blocking Plasmodium falciparum transmission but safety concerns have hampered implementation in Sub-Saharan Africa. We, therefore, investigated the safety of age-dosed SLDPQ. Methods: We conducted a randomised, double-blind, placebo-controlled, non-inferiority trial of SLDPQ combined with either artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPP) in Ugandan and Congolese children aged 6m−11y with acute uncomplicated P. falciparum and haemoglobin (Hb) concentrations ≥ 6 g/dL. A comorbid illness requiring inpatient treatment, on haemolysing drugs in glucose-6-phosphate dehydrogenase deficiency (G6PDd), allergy to study drugs, and enrolment in another trial excluded participation. G6PD status was defined by genotyping for the c.202T A- G6PDd allele. Randomisation was stratified by age and G6PD status. The development of profound (Hb <4 g/dL) or severe anaemia (Hb <5 g/dL) with severity features, within 21 days of treatment, defined the primary end point. The sample size assumed a 1·5% incidence in the placebo arm and a 3% non-inferiority margin. Analysis was by intention to treat. Findings: 1,137 children, median age 5y, were recruited: 286 AL+SLDPQ, 286 AL+Placebo, 283 DHAPP+SLDPQ and 282 DHAPP+Placebo (266, 272, 264, 264 completed the study, respectively): 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (G6PDd group), 119 heterozygous females, 418 G6PD-c.202C normal males (n=418) and females (n=299), and unknown status 17. None developed profound anaemia and three severe anaemia: G6PDd group 0/133 (0%, Placebo) vs. 1/151 (0·66%, SLDPQ): ∆= -0·66% (95% CI -1·96%, 0·63%, p=0·35), and nonG6PDd group: 1/430 (0·23%, Placebo) vs. 1/407 (0·25%, SLDPQ): ∆= -0·014% (95% CI -0·68%, 0·65%; p=0·97). Ten [0·88 (0·42, 1·61%)] patients were transfused in the first week; four had G6PDd. Early vomiting rates (p=0·525) were 22/568 [3·9 (2·4, 5·8)%, Placebo] vs. 18/569 [3·2 (1·9, 5·0)%, SLDPQ]. Interpretation: Gametocytocidal, age-dosed SLDPQ was well tolerated in falciparum-infected African children and had a similar safety profile as placebo. These data support the wider implementation of SLDPQ in Africa. Funding: The study was funded by the Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (Grant Ref: MR/P006973/1