PROMOTE CHEMOPREVENTION

A RANDOMIZED CONTROLLED TRIAL OF MONTHLY DIHYDROARTEMISININ-PIPERAQUINE VERSUS MONTHLY SULFADOXINE-PYRIMETHAMINE VERSUS DAILY TRIMETHOPRIM-SULFAMETHOXAZOLE VERSUS NO THERAPY FOR THE PREVENTION OF MALARIA

Recruitment of study participants began June 28th, 2010 and was completed on July 15th, 2011. Study activities are expected to continue until July, 2014.

ClinicalTrials.gov Identifier:NCT00948896

Young African children living in high transmission areas suffer the greatest burden of malaria. In most African countries, such as Uganda, the only current preventive measure against malaria in high transmission settings is the use of insecticide treated bed nets. Chemopreventive strategies offer a potential means of reducing the burden of malaria among young children living in a high transmission setting. In this study, we will compare the efficacy and safety of 3 promising chemopreventive strategies with the current standard of no chemoprevention. One treatment arm will consist of daily TS, a strategy which has been shown to be effective and is now the standard of care in HIV-infected children. Another treatment arm will consist of monthly SP. IPT with SP in infants has been shown to be effective and is currently undergoing large scale Phase III trials in Africa (http://www.ipti-malaria.org/). We have chosen a monthly dosing strategy for SP in this study because previous studies have shown that the greatest benefits were seen during the first month following dosing. Another treatment arm will consist of monthly dosing of the new ACT regimen, DP. We have included this treatment arm because previous studies have shown this drug to be highly effective for the treatment of malaria, with excellent post-treatment prophylaxis over the month following therapy. This study will be conducted in two distinct patient populations: 1) HIV-unexposed children (HIV-uninfected children born to HIV-uninfected mothers) and 2) HIV-exposed children (HIV-uninfected children born to HIV-infected mothers). The rationale for including both of these populations is that there are importance difference in the current standard of care which could modify and effect of our intervention, and therefore the implications of our results. The current standard of care for HIV-unexposed children living in endemic areas of Africa is not to provide chemopreventive therapy. These children are thought to be relatively protected from developing symptomatic malaria during the first few months of life due to the presence of fetal hemoglobin and placental transfer of maternal antibodies. Therefore, the intervention will begin in HIV-unexposed children when they reach 6 months of age, the time at which the incidence of malaria begins to increase. The intervention will be continued until the children reach 24 months of age, which our prior data suggest is when the incidence of malaria begins to decline due to the development of semi-immunity. In addition we will follow study participants for one additional year following chemopreventive therapy to examine for "rebound" in the incidence of malaria following our intervention.

In contrast to the HIV-unexposed children, the standard of care among HIV-exposed children is to provide TS prophylaxis for the duration of breastfeeding. TS prophylaxis has been shown to be effective for the prevention of malaria. Current recommendations are that HIV-exposed children are retested for HIV approximately 6 weeks after the cessation of breastfeeding and if they remain HIV-uninfected, TS prophylaxis is stopped. It is unknown what effect TS prophylaxis during breastfeeding has on the development of naturally acquired antimalarial immunity among HIV-exposed children. It may be that HIV-exposed children develop immunity during the time they are taking TS prophylaxis and therefore would be expected to have less benefit from extended chemoprevention relative to HIV-unexposed children. Alternatively the use of TS prophylaxis may prevent the development of immunity and therefore place children at particular risk for malaria following cessation of TS, a scenario where extended chemoprevention may be of particular benefit. In this study, HIV-exposed children will begin the intervention when they have completed breastfeeding and have been confirmed to remain HIV-uninfected. The intervention will continue until study participants reach 24 months of age and then the study participants will be followed for on additional year to examine for rebound in the incidence of malaria (similar to the HIV-unexposed children).

It is anticipated that the results of this study will provide valuable comparative data on the effect of different chemopreventive strategies on malaria incidence in two distinct patient populations at high risk for malaria. In addition it is anticipated the results of this study will provide insight into the development of naturally acquired antimalarial immunity in the setting of chemopreventive therapy that will differ in terms of the drug regimens, the age at which the intervention is started, and the HIV status of the mothers.
The study aims are:

Specific Aim 1. To compare the incidence of malaria among infants and children enrolled at 4-6 months of age and randomized to receive no chemoprevention, daily TS, monthly SP, or monthly DP until they reach the age of 24 months. We will test the hypotheses that infants and children who receive chemopreventive therapy will have a lower incidence of malaria compared to those given no chemopreventive therapy, and that the optimal chemopreventive measure will be monthly therapy with the new artemisinin-based combination DP. Secondary outcomes will include comparisons of the incidence of complicated malaria, hospitalizations, diarrheal illnesses and respiratory tract infections; prevalence of anemia, asymptomatic parasitemia, and gametocytemia; and response to antimalarial therapy.

Specific Aim 2. To compare the incidence of adverse events among infants and children enrolled at 4-6 months of age and randomized to receive no chemoprevention, daily TS, monthly SP, or monthly DP until they reach the age of 24 months. We will test the hypothesis that the incidence of adverse events related to study drugs will be lower in infants and children who receive monthly DP compared to those receiving monthly SP and daily TS. Secondary outcomes will include comparisons of the incidence of serious adverse events related to study drugs and the risk of discontinuation of study drugs.

Specific Aim 3. To compare the incidence of malaria among children for 1 year following intervention with no chemoprevention, daily TS, monthly SP, or monthly DP. A concern with chemopreventive therapy is a potential increased risk of malaria after therapy is discontinued due to decreased antimalarial immunity, and this risk may be greatest with continuous chemoprophylaxis. We will test the hypothesis that compared to children who received no chemopreventive therapy, those previously given chemoprophylaxis (daily TS), but not those given IPT (monthly SP or DP), will have a higher incidence of malaria. Secondary outcomes will include comparisons of the incidence of complicated malaria, hospitalizations, diarrheal illnesses and respiratory tract infections; prevalence of anemia, asymptomatic parasitemia, and gametocytemia; and response to antimalarial therapy.