A trial of the benefit of including azithromycin in the drug combination used for seasonal malaria chemoprevention in African children

Good progress is being made in controlling malaria in Africa but success has been only partial. In some countries there has been only a modest decline in the incidence of malaria despite the widespread deployment of insecticide treated bed nets , spraying of the inside of houses with insecticide and treatment of clinical cases with highly effective drug combinations based on compounds derived from the plant Artemisia annua . More efforts need to be made to scale up these interventions but additional control tools are needed. One potential new tool is seasonal malaria chemoprevention (SMC). SMC involves the administration of a treatment dose of an effective antimalarial drug combination to all children at risk during a period of maximum risk of infection. This approach to malaria control is targeted specifically at areas where malaria transmission is limited by climatic factors to only a few months of the year so that drugs do not have to be given on more than three or four occasions. Areas where SMC would be an appropriate intervention include most of the Sahel and sub-Sahel (population approximately 200 million). Studies conducted in areas of seasonal malaria transmission have shown that SMC with the combination of sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) reduced the incidence of severe and uncomplicated malaria by over 70% and probably reduced deaths. The intervention was safe, well tolerated and highly cost effective. Anti-malaria drugs were given successfully and safely by village volunteers. A WHO Policy Advisory Committee has recently reviewed the results of trials of SMC and is likely to recommend this as a malaria control intervention for areas with highly seasonal malaria transmission.
Despite the success of SMC with SP and AQ in reducing malaria, children in the trials of this intervention still suffered many episodes of infectious diseases, some severe and some fatal. It is likely that the majority of these severe illnesses were caused by bacterial infections. Thus, it is possible that adding an antibiotic to the treatment regimen used for SMC could provide added benefit by preventing severe bacterial infections and hence reducing severe illnesses and perhaps deaths. The most suitable antibiotic to be used in this way is azithromycin (AZ). AZ has been given as mass treatment to millions of healthy children to control trachoma (a bacterial eye infection that can lead to blindness) and shown to be safe and well tolerated. Surprisingly, when AZ was deployed in a trachoma elimination programme in Ethiopia, overall child mortality fell by approximately 65%. If AZ really does prevent deaths in young children, it is likely that it does so by preventing bacterial infections, particularly those caused by the pneumococcus, an important cause of death and severe illnesses in young African children. Thus, it is biologically plausible that adding AZ to SMC regimens might provide additional benefit.
To test this hypothesis, a trial will be conducted in approximately 16,000 children in areas of Burkina Faso and Mali where malaria transmission is highly. Children will be randomly allocated to receive SMC with SP+AQ either with or without the addition of AZ. Children will be followed carefully throughout the 2013 malaria transmission season (July-October). All deaths or hospital admissions will be recorded and clinic attendances with a febrile illness will be noted. At the end of the transmission season, a random sample of 4,000 children will be examined and tested for malaria and anaemia. Malaria parasites will be tested at this time for their sensitivity to SP and pneumococci, obtained from the nose, for their sensitivity to AZ. The costs of adding AZ to the SMC regimen and its acceptability will be determined.
The results of this trial should establish clearly whether adding AZ to the regimen of SP+AQ used for SMC provides added benefit and, if it does, whether this is safe and cost effective.

An individually randomised, placebo controlled, double-blind trial will be conducted to test the hypothesis that adding azithromycin (AZ) to the regimen of sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) used for seasonal malaria chemoprevention reduces severe morbidity in African children. Following discussions with the study communities and ethical approval, approximately 16,000 children aged 3 -59 months will be individually randomised to receive three courses of SP + AQ with either a single dose of AZ or placebo at monthly intervals during the peak malaria transmission season. Deaths, hospital admissions and clinic attendances with a febrile illness among study children will be documented. At the end of the malaria transmission season, a cross-sectional survey will be conducted in approximately 4,000 randomly selected children who will be tested for anaemia and malaria parasitaemia. Parasites will be tested for molecular markers of resistance to SP. Pneumococci, isolated from the nasopharynx before and after the intervention, will be tested for susceptibility to macrolide antibiotics. The primary end-point of the trial will be the incidence of deaths and or non-injury related hospital admissions during the four-month observation period. Approximately 100 deaths or hospital admissions are anticipated in the SP+AQ alone group. With 8,000 children in each study arm and assuming a 10% loss to follow up, the trial will have 90% power to detect a 40% reduction in deaths or hospital admissions in children who received AZ. Secondary end-points will be the incidence of malarial and non-malarial febrile illnesses and the prevalence of malaria parasitaemia and anaemia at the end of the malaria transmission season. Data will be collected using the Teleform scanning system; standard statistical analyses will be performed. A DSMB will be established to monitor progress of the trial and to approve an analysis plan.

The observation that a single dose of azithromycin (AZ) reduced overall child mortality by 65% during a two-year follow-up period seems implausible. However, the trial was done well and detailed review has not been able to fault the results or to identify any potential confounding factors. If the findings from this trial are generalisable, they are very important and could have a major impact on the way policies to reduce child mortality in Africa are directed in the future. Confirming these results in further large scale mortality trials in different epidemiological situations will take time and be expensive. Therefore, the investigators of the trial described in this proposal have adopted a simpler and quicker approach, focussing on a more frequent end-point than death, namely an infection severe enough to warrant hospital admission. If a positive impact on this end-point is achieved, this will encourage other investigators, and the donors who might support them, to further explore this approach to the prevention of deaths and severe illnesses in African children whilst a negative result would have the reverse effect.
If the results of the trial proposed show that addition of AZ to seasonal malaria chemoprevention (SMC) treatment regimens does have a significant impact on the incidence of severe infections, reducing hospital admissions, and that the intervention is safe and cost effective, this intervention could be a means of saving the lives of many young African children as acute bacterial infections are now the most frequent cause of death in young children in areas of Africa where malaria has been controlled.

Delivery of AZ could be readily implemented in countries of the Sahel and sub-Sahel which decide to introduce SMC into their routine malaria control programmes as an established delivery system would already be in place. Mass drug administration (MDA) of AZ in areas where SMC is not being delivered would require an alternative delivery systems but, in many potential target countries, systems for mass delivery of drugs to control schistosomiasis, filariasis, intestinal helminths and trachoma and to deliver Vitamin A already exist and could be used to deliver AZ to children at risk, potentially saving the lives of many young African children.

Conduct of this trial, undertaken primarily by African scientists, will further strengthen the ability of the partners in Burkina Faso and Mali to conduct large scale field trials and to anal;yse their results.