Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial

Abstract

Introduction: More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common.

Methods: Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7.

Results: In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of -0.04 g/dL (95% confidence interval [CI] -0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI -0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24-90) reduction in gametocyte carriage (P = .013).

Conclusion: Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia.

Clinical trial registration: PACTR201411000937373 (www.pactr.org).

Keywords: Senegal; hemoglobin; plasmodium; primaquine; safety.

Figure 1.

Trial profile. In sum, 128 patients were excluded. Reasons for noninclusion: 72: hemoglobin <8 g/dl; 7: intended to leave the study area; 15: did not confirm enrollment; 11: positive pregnancy test; 23: hyperparasitemia. Abbreviations: AL, artemether-lumefantrine; ASAQ, amodiaquine-artesunate; DHAPQ, dihydroartemisinin-piperaquine; PQ, primaquine.

Figure 2.

Distribution of the primaquine dose administered to study participants (in mg/kg).

Figure 3.

Mean hemoglobin concentration in G6PD deficient and normal patients who received primaquine or ACT alone. Abbreviations: ACT, artemisinin combination therapy; PQ, primaquine.

Figure 4.

Change in hemoglobin concentration by day 7 (Hb day 7-day 0) plotted against the concentration at baseline, for each group. Abbreviations: ACT, artemisinin combination therapy; PQ, primaquine.

Figure 5.

Gametocyte carriage over 28 days after treatment. A, Prevalence of gametocyte carriage. B, Arithmetic mean gametocyte density. Abbreviation: ACT, artemisinin combination therapy.