Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/17/08/02

Date of Protocol:

01-05-2017

Study Title:	IPTp with dihydroartemisinin-piperaquine and azithromycin for malaria, sexually transmitted and reproductive tract infections in pregnancy in high sulphadoxine-pyrimethamine resistance areas in Kenya, Malawi and Tanzania: an international multi-centre 3-arm placebo-controlled trial
Study Objectives:	PRIMARY OBJECTIVE To determine if IPTp with DP, either alone or combined with AZ, for the control of malaria and STIs/RTIs in pregnancy is safe and superior to IPTp with SP for reducing adverse pregnancy outcomes SECONDARY OBJECTIVES To determine if IPTp with DP plus AZ, is superior to IPTp with DP alone for reducing adverse pregnancy outcomes. To determine the safety of monthly IPTp with DP by conducting nested cardiac monitoring study to specifically address whether previously documented transient QTc prolongation associated with DP increases in magnitude with subsequent courses as well as monitoring adverse drug reactions and adverse/severe adverse events. To conduct, on completion of the trial, a prospective meta-analysis combining the evidence from this and previous trials to provide (with≥80% power) definitive evidence on whether IPTp with DP is superior to the existing strategy of IPTp with SP for controlling malaria and reducing adverse pregnancy outcomes in areas with intense year-round malaria transmission and high SP resistance. To determine if the level of SP drug resistance, assessed by molecular markers, affects the potential impact of IPTp-DP or IPTp with DP+AZ relative to IPTp-SP. To determine the efficacy of IPTp with DP+AZ on curable sexually-transmitted and reproductive -tract infections (STIs/RTIs) relative to IPTp with SP and DP alone. To determine the effect of SP and AZ on the intestinal and vaginal microbiomes of mothers, and the intestinal microbiomes of neonates relative to DP alone. To determine the effect of multiple doses of AZ on the prevalence of macrolide resistance in the pneumococcus. To build trial research capacity in Kenya, Malawi and Tanzania.
Laymans Summary:	Context of the research: Each year over 30 million pregnancies occur in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The control of malaria in pregnancy in parts of East and southern Africa is under threat. Pregnant women are often infected with malaria without showing any outward signs or symptoms which, if left undetected and untreated, can cause anaemia and interfere with the development of the foetus leading to loss of the pregnancy, or premature birth and low birth weight, which in turn increases the risk of early infant death. The World Health Organisation (WHO) therefore recommends a preventive strategy called ‘intermittent preventive treatment in pregnancy’ (IPTp) in which mothers receive a single dose of 3 tablets of medication called sulphadoxine-pyrimethamine (SP) at each scheduled antenatal visit starting in the 2nd and 3rd trimester. However, the effectiveness of this strategy is being compromised due to high levels of resistance to SP in the malaria parasite population. The recent search for safe, effective and well-tolerated alternatives drugs has proven elusive because most of the new candidates tested were not tolerated well enough to be used for preventive purposes. Other trials evaluating test and treat strategies have also proven disappointing. All hopes are now pinned on an antimalarial called dihydroartemisinin-piperaquine (DP), which is known to be safe in the 2nd and 3rd trimester of pregnancy and highly effective for treatment of clinical malaria. Two exploratory trials showed that DP, when taken as IPT by pregnant women, was well tolerated and much more effective than SP in preventing malaria. However, these two trials were not big enough to to evaluate the impact on the pregnancy outcome and the health of the newborn. WHO reviewed the evidence in July 2015 and concluded that DP is indeed a promising alternative to SP and recommended that a larger, confirmatory, trial is needed, before it can consider whether to recommend this drug as an alternative to SP in areas of high resistance. Sexually transmitted and reproductive tract infections (STIs/RTIs) also cause poor birth outcomes and are highly prevalent in East and Southern Africa, and similar to malaria, remain mostly asymptomatic, and therefore undetected and untreated. We will therefore determine whether combining DP with azithromycin, a broad spectrum antibiotic active against STIs/RTIs, can further improve birth outcomes, potentially paving the way for integrated control strategies for malaria and curable sexually transmitted and reproductive tract co-infections. Study aims and objectives: This multi-centre trial will enrol about 4,680 pregnant women in 10 hospitals in Kenya, Tanzania and Malawi and compare the safety, tolerance and beneficial effects of IPTp with DP alone, or combined with azithromycin, to the current strategy with sulphadoxine-pyrimethamine in reducing pregnancy loss, low birthweight, preterm birth and small-for-gestational-age babies, and early infant deaths. Potential applications and benefits: After a decade of trials to find new prevention strategies for malaria in pregnancy, DP has been shortlisted as the only potential alternative to SP for IPTp, but evidence of its benefits on infant outcomes is needed. Combining antimalarial and antibiotic interventions will potentially pave the way for integrated control strategies for malaria and curable sexually transmitted and reproductive tract co-infections. A positive result may lead to a direct policy change by the WHO in countries experiencing high level of parasite resistance, including most countries in East and southern Africa, benefiting women at risk of malaria in these regions resulting in healthier pregnancies and healthier newborns.
Abstract of Study:	Malaria in pregnancy has devastating consequences for mother and foetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for asymptomatic women, but high-level SP resistance threatens its efficacy. Over the last decade, several IPTp trials showed that neither amodiaquine, mefloquine, nor chloroquine-azithromycin are suitable replacements for SP because of their poor tolerability as IPTp. Furthermore, intermittent screening for malaria and treatment with artemisinin-based combination therapies has recently shown to be non-superior to IPTp-SP even in areas with very high SP resistance. Thus, there is an ever urgent need to find alternative drugs for IPTp. Dihydroartemisinin-piperaquine (DP) has the potential to replace SP for IPTp. Exploratory trials from Kenya and Uganda showed that IPTp-DP was more effective than SP in reducing malaria infection (Incidence Rate Ratio [IRR]=0.32) and clinical malaria (IRR=0.16), but these preliminary trials were not powered to assess birth outcomes. WHO, in July 2015, recommended that definitive multi-centre trials are needed before IPTp-DP can be considered for policy. Sexually transmitted and reproductive tract infections (STIs/RTIs) also cause poor birth outcomes and are highly prevalent in East and Southern Africa, and similar to malaria, remain mostly asymptomatic, and therefore undetected and untreated. We will therefore determine whether combining DP with azithromycin, a broad spectrum antibiotic active against STIs/RTIs, can further improve birth outcomes, potentially paving the way for integrated control strategies for malaria and curable sexually transmitted and reproductive tract co-infections. This is a multi-national, individually-randomized, 3-arm, partially-placebo controlled superiority trial comparing the efficacy, safety and tolerance of IPTp-SP (control) versus IPTp-DP, alone or combined with azithromycin (0.5 gr/daily for 3 days) to adverse effects of malaria and curable STIs/RTIs in 4,680 women in 10 sites in high SP resistance areas in Kenya, Malawi, and Tanzania. The study is powered (90%, alpha=0.025) to detect a 25% reduction (RR=0.75) in ‘adverse pregnancy outcomes’ (composite of foetal loss, small-for-gestational age, low birthweight, preterm, or neonatal death). The project includes cardiac monitoring for safety, assessment of antimalarial druge and macrolide resistance, nutritional outcomes, and the impact of SP and AZ on vaginal and intestinal microbiota, and health economics.
1	Malaria in pregnancy has devastating consequences for mother and foetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for asymptomatic women, but high-level SP resistance threatens its efficacy. Over the last decade, several IPTp trials showed that neither amodiaquine, mefloquine, nor chloroquine-azithromycin are suitable replacements for SP because of their poor tolerability as IPTp. Furthermore, intermittent screening for malaria and treatment with artemisinin-based combination therapies has recently shown to be non-superior to IPTp-SP even in areas with very high SP resistance. Thus, there is an ever urgent need to find alternative drugs for IPTp. Dihydroartemisinin-piperaquine (DP) has the potential to replace SP for IPTp. Exploratory trials from Kenya and Uganda showed that IPTp-DP was more effective than SP in reducing malaria infection (Incidence Rate Ratio [IRR]=0.32) and clinical malaria (IRR=0.16), but these preliminary trials were not powered to assess birth outcomes. WHO, in July 2015, recommended that definitive multi-centre trials are needed before IPTp-DP can be considered for policy. Sexually transmitted and reproductive tract infections (STIs/RTIs) also cause poor birth outcomes and are highly prevalent in East and Southern Africa, and similar to malaria, remain mostly asymptomatic, and therefore undetected and untreated. We will therefore determine whether combining DP with azithromycin, a broad spectrum antibiotic active against STIs/RTIs, can further improve birth outcomes, potentially paving the way for integrated control strategies for malaria and curable sexually transmitted and reproductive tract co-infections. This is a multi-national, individually-randomized, 3-arm, partially-placebo controlled superiority trial comparing the efficacy, safety and tolerance of monthly IPTp-SP (control) versus monthly IPTp-DP, alone or combined with a single course of azithromycin at enrolment (1gr/daily for 2 days) to reduce the adverse effects of malaria and curable STIs/RTIs in 4,680 women in 10 sites in high SP resistance areas in Kenya, Malawi, and Tanzania. The study is powered (80%, alpha=0.05) to detect a 20% reduction (RR=0.80) in ‘adverse pregnancy outcomes’ (composite of foetal loss, small-for-gestational age, low birthweight, preterm, or neonatal death). The project includes cardiac monitoring for safety, assessment of antimalarial drug and macrolide resistance, nutritional outcomes and the impact of SP and AZ on vaginal and intestinal microbiota.