Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa (IMPROVE)

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

Kamuzu University of Health Sciences, Kenya Medical Research Institute, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, National Institute for Medical Research, Tanzania, Kilimanjaro Christian Medical Centre, Tanzania, University of Copenhagen, Centers for Disease Control and Prevention, London School of Hygiene and Tropical Medicine, University College, London, Tampere University, University of Bergen, University of Massachusetts, Worcester, University of Toronto, University of Melbourne, Foundation for Innovative New Diagnostics, Switzerland

This study evaluates the efficacy and safety of monthly intermittent preventive treatment using dihydroartemisinin piperaquine (DP) alone or in combination with azithromycin (AZ) compared to sulphadoxine-pyrimethamine (SP) for the prevention of malaria in pregnant women in the second and third trimester.

Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is one of the pillars of malaria prevention in pregnancy in sub-Saharan Africa, in addition to prompt case management and use of long lasting insecticide treated bednets. However, mounting resistance to SP by Plasmodium falciparum increasing renders IPTP-SP ineffective. Two exploratory trials in Uganda and Kenya demonstrated that IPTp with DP was superior to IPTp-SP for the prevention of malaria infection in pregnancy. However, neither study was adequately powered to look at adverse birth outcomes. This study is a confirmatory efficacy trial in Malawi, Tanzania and Kenya to determine the efficacy and safety of IPTp with DP alone or in combination with AZ. This will be a 3-arm trial, superiority, partial blinded, placebo controlled, randomized trial comparing IPTp with SP, versus IPTp with DP alone, and IPTp with DP+AZ with the following hypotheses: IPTp with DP is superior to IPTp with SP in preventing adverse pregnancy outcomes. The combination of DP with AZ further reduces adverse pregnancy outcomes compared to IPTp with DP alone.

The study will be a partially placebo-controlled involving a single placebo for AZ. To further minimise bias, an objective primary outcome measure will be used and all staff will be masked to the treatment assignment of individual women. The trial statistician will also be masked in regard to the treatment code when he develops the statistical analysis plan and writes the statistical programmes, which will be validated and completed using dummy randomisation codes. The actual allocation will only be provided to the study team after locking of the database and approval of the statistical analysis plan by the independent Data Monitoring and Ethics Committee (DMEC) before they review any trial results. The study statistician conducting the interim analysis will remain masked throughout the analysis.

Stat course of 3 tablets of quality-assured SP (tablets of 500 mg of sulphadoxine and 25 mg of pyrimethamine) at each scheduled antenatal visit

Dihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + placebo AZ at each scheduled antenatal visit

Dihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + AZ tablet [1.5g over 3 days as 500mg per day] at each scheduled antenatal visit.

Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo

Women randomised to this intervention will receive stat dose of 3 tablets of 500 mg sulphadoxine and 25 mg of pyrimethamine each (total dose of 1,500mg sulphadoxine and 75mg pyrimethamine) on a single day of clinic visit

Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)

Composite of foetal loss (spontaneous abortion or stillbirth), or singleton live births born small-for-gestational age (SGA), or with low birthweight (LBW), or preterm (PT) (SGA-LBW-PT), or subsequent neonatal death by day 28.

Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR

Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery

QTcF-prolongation of more than 60ms between baseline DTcF prior to first dose of DP (+/- AZ) on day 0 and repeat QTcF 4 - 6 hrs after administration of 3rd dose of DP(+/- AZ) on day 2, or QTcF > 480ms, 4 - 6 hours after on day 2 treatment administration. Only on the DP containing arms.

The death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.

Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit

Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery

Prevalence and incidence of SP and artemisinin resistance markers from infection isolates after enrollment and at delivery

Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis)

Prevalence and incidence of STIs/RTIs (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) at randomization and last antenatal visit prior to delivery

Prevalence and incidence of carriage of macrolide resistant pneumococcus at randomization and delivery

Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant.

Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota

Inclusion Criteria: Pregnant women between 16-28 weeks' gestation Viable singleton pregnancy Resident of the study area Willing to adhere to scheduled and unscheduled study visit procedures Willing to deliver in a study clinic or hospital Provide written informed consent Exclusion Criteria: Multiple pregnancies (i.e. twin/triplets) HIV-positive Known heart ailment Severe malformations or non-viable pregnancy if observed by ultrasound History of receiving IPTp-SP during this current pregnancy Unable to give consent Known allergy or contraindication to any of the study drugs

Individual, de-identified participant data will be made available for meta-analyses as soon as the data analysis is completed, with the understanding that results of the meta-analysis will not be published prior to the results of the individual trial without prior agreement of the investigators. No later than 5 years after the publication of the trial a fully de-identified data set will be available for sharing purposes

Mtove G, Abdul O, Kullberg F, Gesase S, Scheike T, Andersen FM, Madanitsa M, Ter Kuile FO, Alifrangis M, Lusingu JPA, Minja DTR, Schmiegelow C. Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns. Acta Obstet Gynecol Scand. 2022 Mar;101(3):293-302. doi: 10.1111/aogs.14323. Epub 2022 Feb 13.