Improving the radical cure of vivax malaria: A multicentre randomised comparison of short and long course primaquine regimens

间日疟原虫疟疾是亚洲、南美洲和非洲资源贫乏的疟疾流行地区的一个主要发病原因，也是造成死亡的一个重要因素。间日疟的最大负担是在南亚和东南亚，那里有28.5亿人处于危险之中，每年有1亿至3亿例间日疟病例。间日疟原虫引起与贫血恶化相关的反复发热性疾病，特别是在幼儿和孕妇中。严重贫血和出生体重不足导致直接和间接死亡。尽管受间日疟影响的人口非常多，并造成社会经济负担，但它一直是并将继续是一种被忽视的疾病; 2007-2009年期间，全球疟疾研发支出中用于防治间日疟的支出仅占疟疾总支出的3%。自20世纪50年代以来，氯喹一直是治疗急性间日疟的主要药物。然而，对氯喹的耐药性首先在印度尼西亚的巴布亚报告，现在有充分的证据表明，它在印度尼西亚群岛普遍存在，并已蔓延到间日疟流行的大部分地区。与恶性疟原虫不同的是，间日疟原虫除了血液阶段外，还有一个肝脏阶段的寄生虫（称为催眠虫），能够在初次感染后数周甚至数月内苏醒。间日疟的完全治疗需要施用抗疟药以根除血液和肝脏阶段的寄生虫。伯氨喹仍然是市场上唯一一种具有肝脏阶段活性的药物。然而，伯氨喹耐药性的疗效难以确定，这是由于间日疟原虫的复发模式不同，需要长期随访以捕获晚期复发。伯氨喹的广泛使用受到严重限制，因为人们担心其有效性和安全性。伯氨喹会导致G6 PD缺乏症患者的溶血，这是一种遗传性疾病，在流行区有5-35%的患者发生。有几个现成的，负担得起的和可靠的诊断工具，用于快速检测GPD缺乏症，因此临床医生往往不愿意开一个治疗，这是潜在的有害与有限的感知效益。当它被规定遵守目前推荐的14天治疗方案是穷人。该提案旨在为伯氨喹的使用提供关键证据，伯氨喹是一种越来越被认为是全球抗击疟疾的关键工具的药物。我们假设疗程短、剂量大的伯氨喹治疗方案将提供一种安全有效的抗复发治疗方法。我们的随机安慰剂对照多中心试验将在5个亚洲国家比较伯氨喹与单用杀线虫剂治疗的两种不同方案。将在南亚建立试验中心（印度、巴基斯坦和阿富汗），70%的病例发生在这些国家，间日疟复发的间隔相对较长，以及东南亚的两个站点（越南和印度尼西亚）其中复发之间的间隔较短，复发的风险较大。主要目的是比较两种伯氨喹方案，在7或14天符合入选标准的单纯间日疟患者将被随机分配接受以下三种治疗之一：方案1 -标准血液杀线虫治疗+ 14天监督伯氨喹（7 mg/kg总剂量）;方案2 -标准血液杀线虫治疗+ 7天监督伯氨喹（7 mg/kg总剂量）;方案3 -标准杀线虫治疗。伯氨喹治疗将推迟至随访期结束。这是一个对照方案，在治疗后，患者将被随访12个月，以监测间日疟复发的次数和贫血的程度。每次复发的间日疟将采用相同的分配方案治疗。

Plasmodium vivax malaria is a major cause of morbidity and an important contributor to mortality in poorly resourced endemic areas in Asia, South America and Africa. The greatest burden of vivax malaria is in South and Southeast Asia, where 2.85 billion people are at risk and experience 100 to 300 million cases of vivax malaria each year. Plasmodium vivax causes repetitive febrile illness associated with worsening anaemia particularly in young children and in pregnant women. Severe anaemia and low birth weight resulting in direct and indirect mortality. Despite the very large population affected by vivax malaria and its socioeconomic burden, it has been and continues to be a neglected disease; global malaria R&D spending on combating P. vivax amounted to just 3% of total spending on malaria between 2007-2009. Since the 1950s chloroquine has been the mainstay of treatment for acute vivax malaria. However resistance to chloroquine was first reported in Papua, Indonesia and there is now good evidence that it is prevalent across the Indonesian archipelago and has spread throughout much of the vivax endemic world. Unlike Plasmodium falciparum, P. vivax has in addition to the blood stage a liver stage of the parasite (known as hypnozoite) capable of reawakening weeks or even months after the primary infection. The complete treatment of vivax malaria requires administration of antimalarials to eradicate both the blood and liver stages of the parasite. Primaquine remains the only drug on the market for its liver stage activity. However the efficacy of primaquine resistance is difficult to determine due to variable relapsing patterns of P. vivax and the need for prolonged follow up to capture the late relapses. The widespread use of primaquine has been severely limited because of concerns regarding both its efficacy and safety. Primaquine causes haemolysis in patients with G6PD deficiency, an inherited disorder occurring in 5-35% of patients in endemic zones. There a few readily available, affordable and reliable diagnostic tools for the rapid testing of GPD deficiency, and thus clinicians often reluctant to prescribe a therapy that is potentially harmful with limited perceived benefit. When it is prescribed adherence to the currently recommended 14 day treatment regimen is poor. This proposal aims to provide critical evidence on the use of primaquine, a drug which is being increasingly recognised as a crucial tool in the global fight against malaria. We hypothesise that a shorter course high dose primaquine regimens will provide a practical approach to antirelapse therapy that is safe and effective. Our randomized placebo controlled multicentred trial will compare two different regimens of primaquine against schizontocidal treatment alone in 5 Asian countries. Trial centres will be established in South Asia (India, Pakistan and Afghanistan) where 70% of all cases occur and the interval between vivax relapses is relatively long, as well as two sites from South East Asia (Vietnam and Indonesia) where the interval between relapses is shorter and the risk of relapse greater.The primary objective will be to compare two primaquine regimens giving the same total dose primaquine over either 7 or 14 days. Patients presenting with pure vivax malaria, meeting the inclusion criteria will be randomly assigned to receive one of the following three treatments:Option 1 - Standard blood schizontocidal therapy + 14 days of supervised primaquine (7mg/kg total dose).Option 2 - Standard blood schizontocidal therapy + 7 days of supervised primaquine (7mg/kg total dose).Option 3 - Standard schizontocidal therapy. Treatment with primaquine will be deferred until the end of the follow up period. This is the control regimen.Following treatment, patients will be followed for 12 months to monitor the number of vivax recurrences and the level of anaemia. Each recurrence of vivax malaria will be treated with the same allocated regimens.