Creative solutions to extraordinary challenges in clinical trials: methodology of a phase III trial of azithromycin and chloroquine fixed-dose combination in pregnant women in Africa

摘要: Malaria in pregnancy is one of the most common preventable causes maternal and neonatal morbidity mortality sub-Saharan Africa. To prevent its adverse effects, such as anaemia, placental parasitaemia low birth weight (LBW) neonates, World Health Organization recommends effective malaria case management, use insecticide-treated bed nets intermittent preventive therapy (IPTp). Sulphadoxine-pyrimethamine (SP) has been standard for IPTp several countries, but parasite resistance to SP growing. Therefore, new therapies are urgently needed. One candidate being evaluated a fixed-dose combination azithromycin chloroquine (AZCQ). This paper describes challenges innovative solutions implemented designing conducting pivotal AZCQ-IPTp trial, sponsored by Pfizer Inc co-funded Medicines Venture. The trial multicentre, multicountry, phase III, open-label, randomized superiority study versus SP-IPTp pregnant women was designed meet stringent regulatory agency scientific advice policy makers’ recommendations, incorporates an adaptive design manage programme risk, maintain operating characteristics optimize resources. trial’s novel composite primary endpoint proportion participants with suboptimal outcome (abortion [≤28 weeks], stillbirths [>28 weeks], premature [<37 weeks] deliveries, LBW [<2,500 g] live missing data or loss follow-up). employs prospective group sequential three unblinded analyses when 50%, 70% 100% achieve endpoint; team will remain blinded until after completion study. number be adaptive, based on review observed pooled across two treatment arms, approximately 1,000 complete assessments. ongoing expected 2014. report unique this which may serve prototype future other studies involving similar conditions.