Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China

Malaria Journal Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China Hui Liu 0 Heng-lin Yang 0 Jian-Wei Xu 0 Jia-zhi Wang 1 Ren-hua Nie 0 Chun-fu Li 0 0 Yunan Institute of Parasitic Diseases , Puer 665000 , China 1 Tengchong County Center for Disease Control and Prevention , Tengchong , China Background: Plasmodium vivax is the main malaria parasite in China, and China is now making efforts to eliminate malaria by 2020. Radical cure of vivax malaria is one of challenges for malaria elimination. The purpose is to evaluate the efficacy and safety of artemisinin-naphthoquine (ANQ) versus chloroquine-primaquine (CQ-PQ) in treatment of vivax malaria in Yunnan Province, China. Methods: An open-label randomized and non-inferiority design, eligible patients with monoinfections of P. vivax were randomly assigned to receive either a total target dose of ANQ 24.5 mg/kg (naphthoquine 7 mg/kg and artemisinin 17.5 mg/kg), once a day for three days, or a total CQ dose of 24 mg base/kg, once a day for three days plus a PQ dose of 0.45 mg base/kg/day, once a day for eight days. Patients were followed up for one year. The difference in efficacy between ANQ and CQ-PQ was compared via Wilson's test. Results: By day 42, the number of patients free of recurrence was 125 (98.4%; 95% Confidence interval, 94.4-99.8%) for ANQ arm and 123 (96.1%; 95%CI, 91.1-98.7%) for CQ-PQ, and non-significant (P = 0.4496). By day 365, the number was 101 (79.5%; 95%CI, 71.8-85.9%) for ANQ and 106 (82.8%; 95%CI, 75.1-88.9%) for CQ-PQ, and non-significant (P = 0.610). So the proportions of patients free of recurrence had no significant difference between ANQ and CQ-PQ groups by day 28, 42 and 365; compared with CQ-PQ, the side effect of ANQ was mild. Conclusion: ANQ is non-inferior to CQ-PQ in terms of patients free of recurrence, and safer than CQ-PQ. Plasmodium vivax; Artemisinin-naphthoquine; Efficacy; Safety - Background Plasmodium vivax is the main malaria parasite in China. Yunnan Province is a vivax and falciparum malaria coendemic region and one of two provinces with endemic falciparum malaria. China is now making efforts to eliminate malaria by 2020 [1,2]. Radical cure of vivax malaria is one of challenges for malaria elimination [3]. The treatment regimen, chloroquine (CQ) for blood stage infection and 8-aminoquinoline for liver stage parasite is often poorly adhered to [4,5]. Further, since CQ-resistant P. vivax was first described in 1989 in Papua New Guinea [6], the decline in the efficacy of CQ has been reported in some geographical sites [7]. In general, the use of artemisinin-based combination therapy (ACT) has been limited to patients with falciparum malaria and showed advantages in terms of adherence and safety [8-11]. However, with the high number of misdiagnoses in routine practice and the rise and spread of CQ-resistant P. vivax, there might be a compelling rationale for a unified ACT strategy for vivax and falciparum malaria in all co-endemic regions [12]. The use of ACT for patients with vivax malaria has been evaluated in China [13], Papua, Indonesia [14], Thailand [7] and Ethiopia [15]. These study results have documented that ACT was effective, safe and well-tolerated in the treatment of vivax malaria. In the context, an open-label randomized and non-inferiority trial was conducted to assess whether artemisininnaphthoquine (ANQ) is as effective as chloroquineprimaquine (CQ-PQ), safer than CQ-PQ in treatment of patients with P. vivax monoinfections in Yunnan Province, China. Methods Patients From February 2009 to December 2010, patients were recruited into our open-label randomized study at Tengchong County Center for Disease Control and Prevention, and Tengchong County Hospitals at the China-Myanmar border. The local transmission is from June to September in most parts of Tengchong County. Because of in malaria pre-elimination phase and an altitude higher than 2,000 m, there was only imported malaria and rarely local infection in recent years. Patients older than five years of age who weighed more than 15 kg and presented with single P. vivax malaria (parasite density 400100,000 parasites per L) were enrolled into the study. Patients were not admitted to the study if any the following criteria present: (1) pregnancy, (2) severe malaria, (3) having taken any anti-malarial drug within the past 14 days, (4) history of hypersensitivity to any of the study drugs, (5) severe dysfunction of kidney, liver and heart, (6) residence living at an altitude lower than 2,000 m, (7) unable to follow up. Allocation As soon as confirmed patients were enrolled into the study, they were randomly assigned to receive either ANQ or CQ-PQ regimens. A researcher, who did not have a role in recruitment, put sealed envelopes in blocks of 50 (25 ANQ and CQ-PQ respectively) in a box, and an enrolled patient drew an envelope from it to achieve treatment allocations in equal numbers. When the box was empty, another 50 envelopes were added. Drugs ANQ was registered by Food and Drug Administration, China as GYZZ H20050270 and licensed to Kunming Pharmaceutical Corp to produce. A tablet of ANQ is composed of 50 mg naphthoquine and 125 mg artemisinin. CQ was registered as GYZZ H31020423 and PQ as GYZZ H2005984 in China. CQ-PQ was produced and pre-packed by Shanghai Sino-West Pharmaceutical Corp. Both ANQ and CQ-PQ were administered following the anti-malarial drug policy of China. Based on the hypothesis that a three day dosing could reduce recurrence of Plasmodium vivax, ANQ was given once a day for three days, with a total target dose of 24.5 mg/kg (naphthoquine 7 mg/kg and artemisinin 17.5 mg/kg). CQ was given once a day for three days with a total target dose of 24 mg base/kg and PQ was offered once a day for eight days with a dose of 0.45 mg base/kg/day. Follow-up The researchers visited all patients every 8 hrs for the first three days. Axillary temperatures were measured every 8 hrs after treatment until after 48 hrs of fever clearance. Thick and thin blood smears were taken and examined every 8 hrs in each active visit, and then day 7, 14, 21 and 28 respectively. The subsequent PQ doses of CQ-PQ groups were given under supervision of patient caretakers one hour after supper and before going to bed from the fourth day. Patients received the remaining PQ doses packed by aluminium-plastic foil and were instructed clearly about their subsequent treatment, emphasizing the importance of taking drugs after food and before going to bed, and taking their medicines even when their symptoms had subsided. The patients were asked to return for treatment in any case that they had dark urine; this was done instead of testing for G6PD deficiency because of shortage of reagent kit and equipment supplies. Patients were visited and interviewed every month; meanwhile blood smears were done during the monthly (...truncated)