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Translational research and clinical trials according to GCP guidelines

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Title Translational research and clinical trials according to GCP guidelines
Period 12 / 2005 - 08 / 2010
Status Completed
Research number OND1311788
Data Supplier Nederlandse Organisatie voor Wetenschappelijk Onderzoek - NWO

Abstract

This project aims to build up the capacity for and start with studies into (i) the safety of the newer antimalarial agents during pregnancy and (ii) the efficacy of antimalarial intermittent preventive treatment regimens during pregnancy (IPTp) in women with and without HIV co-infection. (i) will evaluate the short-term safety of new antimalarial regimens for uncomplicated Plasmodium falciparum malaria in pregnancy and the long-term safety by following children after birth. Antimalarial drug pharmacokinetics and pharmacodynamics and drug-drug interactions with antiretroviral (ARV) drugs will be examined. In (ii) an Early Diagnosis and Treatment (EDT) approach will be compared with the standard IPTp two-dose regimen using sulfadoxine/pyrimethamine (SP) in (peri-)urban clinics in Kigali, Rwanda. In Uganda, IPT studies will be set up when the safety of newer regimens has been confirmed. The investigation will also evaluate the degree of P. falciparum drug resistance and the effects of HIV infection and antiretroviral treatment on the efficacy and safety of IPTp. In sub-Saharan Africa, the co-existence of HIV infection and malaria has enormous consequences for health and health services. Pregnant women and children are especially vulnerable to both diseases. HIV infected pregnant women are more susceptible to malaria whereas placental malaria may increase the risk of vertical transmission of HIV. Malaria in pregnancy, often referred to as double trouble, is associated with increased maternal morbidity and mortality and poor neonatal outcome. In high transmission regions, fever does not reliably predict placental malaria and access to early diagnosis and treatment (EDT) of symptomatic malaria is often limited. Therefore, a preferred approach is to provide intermittent presumptive treatment to pregnant women, IPTp. IPTp significantly reduces the rate of neonatal low birth weight (LBW) a strong indicator of poor neonatal outcome, maternal parasitaemia and anaemia and perinatal death, especially in low parity women. IPTp with SP given in the second and the third trimester of pregnancy is currently recommended for entire sub-Saharan Africa. The effectiveness of IPTp in low-transmission areas needs further study, and this also applies to (peri-)urban areas, where primary health care facilities and access to care are generally better than in rural settings. Efficacy and cost-effectiveness of IPTp need to be compared to EDT strategies. Because of its relatively low transmission intensity, Rwanda is one of the few African nations where IPTp is not yet practice, but there is a strong wish to study the effectiveness of IPTp and compare this to EDT. Both treatment of malaria and IPTp are increasingly threatened by parasite resistance to the traditional agents, which were regarded safe in pregnancy, chloroquine and SP. Moreover, the increase of HIV in malaria-endemic areas poses further problems: IPTp regimens for HIV-positive women require more frequent dosages of SP; antimalarials may interact with HAART or antiretroviral regimens used for prevention of mother-to-child transmission (PMTCT) of HIV; AIDS patients are more prone to mount allergic reactions to SP; and co-trimoxazole prophylaxis in women with AIDS may enhance the selection of anti-folate resistant parasite strains. Alternative antimalarial regimens are limited because of the poorly documented safety of the newer drugs during pregnancy. Artemisinin-based combination therapy (ACT) is currently recommended for drug resistant P. falciparum malaria but usage in the first trimester of pregnancy was recently excluded. Questions on safety also apply to amodiaquine and to the components of Lapdap® (chlorproguanil/dapsone). Treatment with Coartem® (artemether/lumefantrine) in pregnancy is currently being studied in Thailand, but not in Africa. Piperaquine, one of the most promising components of ACT has been prescribed at large scale in China but use in pregnancy has not been properly documented. There is no generally accepted format for drug studies in pregnancy and this project will serve as pathfinder. The FDA is working on guidance for pharmaceutical industries and a Malaria in Pregnancy (MiP) Working Group was recently established but both initiatives are still in their infancy. The current opinion is that studies with new drugs in pregnancy should only include patients with a need for treatment. This also requires demonstration that SP resistance demands alternative regimens. Studies should also include a strong pharmacological component. In this project we choose to start with detailed observations in small patient series, because this methodology offers excellent options for training and education. This project was designed to prepare primary health care centres facilities for conducting IPT studies, to improve the existing research capacity at the central level, and to share infrastructure with other closely related projects in this program.

Related organisations

Other involved organisations

Makerere University, Kampala, Uganda
Centre Hospitalier Universitaire de Kigali, Rwanda
IATEC (Kampala office), Uganda
City Council of Kampala, Uganda
Institute for Tropical Medicine
Laboratoire National de Référence, Kampala, Uganda

Related people

Project leader Prof.dr. J.M.A. Lange

Classification

A34800 Drugs and pesticides
A73200 Second-line health care
A76000 Patients care
C20000 Development studies
D23110 Infections, parasitology
D23220 Internal medicine
D23340 Biopharmacology, toxicology
D23361 Neonatology
D24000 Health sciences

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