Last Updated: 24/11/2025
IPTp with dihydroartemisinin-piperaquine and azithromycin for malaria, sexually transmitted and reproductive tract infections in pregnancy in high sulphadoxine-pyrimethamine resistance areas (IMPROVE)
Objectives
The overall aim of the study is to provide the WHO with definitive evidence to determine whether monthly IPTp with DP, alone or combined with a single course of AZ at enrolment, is a viable alternative to the current strategy of monthly IPTp with SP in order to improve the outcome of pregnancies in areas with high levels of parasite resistance to SP and moderate to high malaria transmission and prevalence of STIs/RTIs in East and Southern Africa.
This objective will be achieved through:
Primary Objective:
- determining if monthly IPTp with DP, either alone or combined with a single course of AZ at enrolment, for the control of malaria and STIs/RTIs in pregnancy is safe and superior to monthly IPTp with SP for reducing adverse pregnancy outcomes
Secondary Objectives:
- determining if monthly IPTp with DP plus a single course of AZ at enrolment is superior to monthly IPTp with DP alone for reducing adverse pregnancy outcomes.
- determining 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.
- 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.
- 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.
- 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.
- 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.
- determine the effect of AZ on the prevalence of macrolide resistance.
- to build trial research capacity in Kenya, Malawi and Tanzania.
Liverpool School of Tropical Medicine (LSTM), United Kingdom
Kenya Medical Research Institute (KEMRI), Kenya
Malawi College of Medicine, Kamuzu University of Health Sciences (KUHeS), Malawi
Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW), Malawi
National Institute for Medical Research (NIMR) Tanzania, Tanzania
Kilimanjaro Christian Medical University College (KCMUCo), Tanzania
University of Copenhagen (UCPH), Denmark
Centers for Disease Control and Prevention (CDC), United States
London School of Hygiene and Tropical Medicine (LSHTM), United Kingdom
University of Massachusetts (UMass) Amherst, United States
University of Toronto (U of T), Canada
University of Melbourne (UoM), Australia
University of Tampere, Finland
Cardiabase by Banook Group, France
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.
An international, multi-centre, 3-arm, parallel, partially placebo-controlled, individually randomised, phase-3, superiority trial involving 4,680 (1,560 per arm) pregnant women in approximately 10 sites in areas of high malaria transmission and high SP resistance in western Kenya, northern-eastern Tanzania and southern Malawi.
Oct 2016 — Sep 2019
$9.12M
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