EDCTP portfolio: Malaria

The IMPROVE trials should reveal whether a recently developed drug can protect pregnant women from malaria.

Protecting pregnant women from malaria

Some 30 million pregnant women are at risk of malaria in Africa, and 10,000 die from malaria each year. In addition, malaria is responsible for the deaths of 100,000 infants, and 900,000 are born underweight because of malaria infections.

To prevent infections, pregnant women receive a series of preventive treatments with sulfadoxine-pyrimethamine (SP), as well as insecticide-treated bednets. However, resistance to SP is growing, and the hunt is on for safe and effective alternatives. Unfortunately, several possible options have been ruled out because, although they prevent malaria infections, many women experience side effects such as dizziness and vomiting.

The challenge

The IMPROVE team has been exploring the use of a recently developed antimalarial drug, dihydroartemisinin–piperaquine (DP), to replace SP in areas where resistance to SP is high. Small-scale trials in Kenya and Uganda have shown that DP is better than SP at preventing malaria infections and is well-tolerated, but were not large enough to judge the effect of DP on pregnancy outcomes. Trial data were reported to WHO in 2015, which stated that supportive evidence from a large-scale trial was required before DP could be recommended in pregnancy.

In two new larger-scale trials in ten sites in three countries, involving more than 4500 women, the IMPROVE team is aiming to generate confirmatory evidence of DP’s efficacy against malaria infection, as compared with SP, and new data on birth outcomes – such as fetal loss, premature birth and low birthweight. As well as comparing SP and DP, the phase III IMPROVE-1 study has a third arm, which includes the antibiotic azithromycin as well as DP. Azithromycin is used to prevent sexually transmitted and reproductive tract infections, which are common in East Africa and can also affect birth outcomes.

Furthermore, the team is running a complementary phase III trial (IMPROVE-2) in pregnant women with HIV, who cannot receive SP because of its interactions with co-trimoxazole, an antibiotic used prophylactically to prevent infection. A previous small-scale study suggested that DP is safe and well-tolerated, but this larger study will show whether it also protects against negative birth outcomes and whether azithromycin provides any further benefits to mother or offspring.

The project

The trials should provide definitive evidence on the suitability of DP as a preventive treatment against malaria in pregnancy. They will also reveal whether azithromycin provides any additional benefits.

Impact


crucial in

widening African

children’s access

to antiretrovirals

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Some 30 million pregnant women are at risk of malaria in Africa, and 10,000 die from malaria each year. In addition, malaria is responsible for the deaths of 100,000 infants, and 900,000 are born underweight because of malaria infections.

To prevent infections, pregnant women receive a series of preventive treatments with sulfadoxine-pyrimethamine (SP), as well as insecticide-treated bednets. However, resistance to SP is growing, and the hunt is on for safe and effective alternatives. Unfortunately, several possible options have been ruled out because, although they prevent malaria infections, many women experience side effects such as dizziness and vomiting.

The IMPROVE team has been exploring the use of a recently developed antimalarial drug, dihydroartemisinin–piperaquine (DP), to replace SP in areas where resistance to SP is high. Small-scale trials in Kenya and Uganda have shown that DP is better than SP at preventing malaria infections and is well-tolerated, but were not large enough to judge the effect of DP on pregnancy outcomes. Trial data were reported to WHO in 2015, which stated that supportive evidence from a large-scale trial was required before DP could be recommended in pregnancy.

In two new larger-scale trials in ten sites in three countries, involving more than 4500 women, the IMPROVE team is aiming to generate confirmatory evidence of DP’s efficacy against malaria infection, as compared with SP, and new data on birth outcomes – such as fetal loss, premature birth and low birthweight. As well as comparing SP and DP, the phase III IMPROVE-1 study has a third arm, which includes the antibiotic azithromycin as well as DP. Azithromycin is used to prevent sexually transmitted and reproductive tract infections, which are common in East Africa and can also affect birth outcomes.

Furthermore, the team is running a complementary phase III trial (IMPROVE-2) in pregnant women with HIV, who cannot receive SP because of its interactions with co-trimoxazole, an antibiotic used prophylactically to prevent infection. A previous small-scale study suggested that DP is safe and well-tolerated, but this larger study will show whether it also protects against negative birth outcomes and whether azithromycin provides any further benefits to mother or offspring.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

The trials should provide definitive evidence on the suitability of DP as a preventive treatment against malaria in pregnancy. They will also reveal whether azithromycin provides any additional benefits.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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