The following paragraphs address our proposed considerations which are: social value; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and harm benefit balance; clinical equipoise; and double standards.
Social value
For any clinical study to be ethically permissible, regardless of whether it is an RCT or if placebo is employed, it must have social value relating to the importance of the information that the study is likely to produce [1]. For the IMPROV study, this is directly related to the disease burden of P. vivax and the knowledge gap in the treatment of the disease. P. vivax is a major cause of morbidity and mortality in endemic countries [9], and was estimated to be responsible for more than 14 million clinical cases globally in 2015 [10]. Much of its morbidity and mortality is attributable to the chronic relapsing nature of the infection arising from reactivation of the dormant liver stages (hypnozoites) of the parasite [11]. Preventing relapse is therefore critical to achieving malaria control and its ultimate elimination. The radical cure of vivax malaria requires treatment of both the blood stages of the parasites as well as the liver stages. The treatment of the blood stage parasites can be achieved safely and effectively with chloroquine or an ACT, however the clearance of the hypnozoites requires a hypnozoitocidal agent, primaquine, which has variable efficacy and potential for serious haemolytic toxicity. Primaquine is the only currently available hypnozoitocidal agent.
Need for a randomised controlled trial and a placebo arm
The next question that needs to be addressed is whether there is need for a randomised controlled trial and whether an active control arm or placebo is more suitable. Without a placebo arm, it is not possible to determine if any of the treatments are effective. Although primaquine has been used clinically for more than fifty years, there are enduring questions regarding its safety and efficacy. Patients remaining in an endemic environment are vulnerable to recurrent infections due to recrudescence from the same partially treated blood stage parasite, reinfection with a new strain, or relapse from a dormant hypnozoite. The frequency and timing of relapses varies considerably with geographical location, from weeks in sub-equatorial regions to more than a year in more temperate climates [12]. Hence a control arm is vital to quantify the background risk of recurrence in the absence of treatment. Without a placebo comparator arm, equivalence between the primaquine regimens could not be used to infer that both regimens were equally efficacious, since they could both be equally useless. Furthermore, since both the disease and primaquine can cause severe haemolysis, the absence of a placebo arm makes it impossible to assess the degree to which haemolysis is attributable to the disease or the drug. In view of these confounding factors, a randomised controlled trial is vital and the non-inclusion of placebo could be considered unethical due to the fallibility of the conclusion and potentially erroneous recommendation that a trial without placebo arm could produce [13].
Standards of care
Another consideration is the standard of care in each location. The WHO recommends treatment with chloroquine or an ACT plus primaquine for 14 days [14]. In reality, primaquine is not adopted widely in endemic areas. Two countries participating in the IMPROV study (Afghanistan and Ethiopia), do not currently recommend primaquine in routine practice. In these areas the ethical justification for the use of the 14-day placebo arm is relatively straightforward. The standard of care is no primaquine. However in countries that do recommend primaquine (Indonesia and Vietnam), the justification of a placebo arm requires further consideration.
In many endemic settings, healthcare providers are reluctant to prescribe primaquine even if it is national policy due to the uncertainty of the glucose-6-phosphate-dehydrogenase (G6PD) status of their patients and the risk of causing severe iatrogenic induced haemolysis [15]. Often the appreciable risks of severe anaemia due to the failure to prevent relapsing infections are not included into the rationale or treatment algorithm. This uncertainty is compounded by uncertainty of the clinical efficacy of the 14-day primaquine regimen, since the quality of evidence for this varies in different locations [13]. Finally, even when primaquine is prescribed appropriately, patient adherence to the 14-day regimen is thought to be poor. The actual standard of care in most endemic areas does not include primaquine, resulting in at least two standards: no primaquine and 14 days primaquine.
Clinical equipoise
Clinical equipoise implies there is true uncertainty within the medical community of the risks and benefits between different study arms [16]. Clinical trials have yielded conflicting results with regard to whether 7-days 1 mg/kg primaquine (total 7 mg/kg) or 14-days 0.5 mg/kg/day primaquine (total also 7 mg/kg) is superior. Some trials have shown that the 7-day (total 7 mg/kg) primaquine regimen is “highly effective” [17], or as effective as the 14-day regimen (also total 7 mg/kg) [18], so it can be argued that there is equipoise between the two primaquine arms. In addition, neither 7-days nor 14-days primaquine has been tested against placebo, further justifying the need for a placebo arm.
Risk of harm due to administration of placebo and harm benefit balance
This section discusses the potential direct harm caused by the administration of placebo. The main harm to an individual patient in the placebo arm is relapse, the frequency of which varies markedly with geographical location. The timing of relapse also varies, ranging from three weeks to more than a year after the initial infection [12]. Unfortunately, there is no reliable data on the timing and frequency of relapse by location, which makes this particular assessment the most difficult of all the considerations we proposed. In the IMPROV study, based on discussions with local collaborators and ethics committees, the maximum number of relapses before a patient is removed from the study is capped at three or four, depending on the site, and all relapsed infections are treated immediately. However this risk of harm is no more than the risk of harm of being treated in the clinic, which, in majority of cases, is treatment without primaquine.
An alternative assessment of harm should include comparison of the potential for direct harm of being in the placebo arm with the potential for direct harm of being in the primaquine arms, of which the most important is the risk of haemolysis. The risk of haemolysis in the 7-day primaquine arm, which has a higher individual daily dose, is theoretically higher than in the 14-day arm. However the only published data on 7-day primaquine usage, where 60 mg/day was administered, showed that this dose was safe and well tolerated [17]. The IMPROV trial excludes G6PD deficient patients from randomisation, but a limited degree of haemolysis which has no clinical significance is expected to occur in all patients, even those who are G6PD normal.
In addition to the above considerations, it is important for any study to ensure that the ancillary care obligations are met and that ancillary risks are minimised. In the IMPROV study, treatment efficacy and patient safety are ensured by close monitoring over a twelve-month follow up period following a schedule of visits and corresponding clinical and laboratory examinations [8].
Double standards
Critics of placebo controlled trials often refer to a controversial series of multinational HIV trials in Sub-Saharan Africa in the 1990s where placebo was used as control when an effective treatment regimen had already been established. This scenario is vastly different from the context of placebo use in P. vivax radical cure. Firstly, good quality primaquine is cheap and widely available in a generic formulation throughout the developing world. In contrast, the main reason for not using the established standard in the AZT trials was its affordability. The HIV trials were designed to translate research findings in wealthy countries into simpler and more affordable treatment regimens in poorly resourced countries. Secondly, no superior radical cure of P. vivax exists in wealthy countries, hence there is no double standard of care [14].