Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Pregnancy, Malaria in Pregnancy, Malaria

Intervention / Treatment
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* Drug: dihydroartemisinin-piperaquine
* Drug: sulphadoxine-pyrimethamine
* Drug: dihydroartemisinin-piperaquine plus azithromycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IPTp-SP<br>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 | Drug: sulphadoxine-pyrimethamine<br>* 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<br>* Other names: Fansidar;|
| Experimental: IPTp-DP<br>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 | Drug: dihydroartemisinin-piperaquine<br>* Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo<br>* Other names: Eurartesim;|
| Experimental: IPTp-DPAZ<br>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. | Drug: dihydroartemisinin-piperaquine plus azithromycin<br>* Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)<br>* Other names: Eurartesim plus Zithromax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse pregnancy outcome | 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. | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of foetal loss and neonatal mortality | Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality | 8 months | 
| SGA-LBW-PT composite | Composite of small for gestational age, low birth weight or preterm birth | 6 months | 
| SGA | Small for gestational age using the new INTERGROWTH population reference's 10th percentile | 6 months | 
| LBW | Low birth weight defined as a corrected birth weight below 2.5 kg | 6 months | 
| PT | Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks | 6 months | 
| Neonatal length and stunting | Neonatal length and stunting | 8 months | 
| Clinical malaria during pregnancy | Incidence of clinical malaria during pregnancy | 6 months from randomisation | 
| Malaria infection during pregnancy detected by microscopy and PCR | Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR | 6 months from randomisation | 
| Composite placental malaria detected by microscopy, by molecular methods or by histology | Prevalence of placental malaria by microscopy, PCR and placental histology | 6 months from randomisation | 
| Placental malaria detected by microscopy | Prevalence of placental malaria detected in maternal placental blood by microscopy | 6 months from randomisation | 
| Placental malaria detected by molecular methods (PCR) | Prevalence of placental malaria detected in maternal placental blood by PCR | 6 months from randomisation | 
| Placental malaria detected by histology | Prevalence of placental malaria detected in full placental section by histology | 6 months from randomisation | 
| Maternal nutritional status | Changes in maternal nutritional status by MUAC and BMI. | 6 months from randomisation | 
| Maternal anaemia during pregnancy and delivery | Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery | 6 months from randomisation | 
| Congenital anaemia | Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood | 6 months from randomisation | 
| Congenital malaria infection | Prevalence of malaria infection by microscopy or PCR from newborn cord blood | 6 months from randomisation | 
| QTc-prolongation | 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. | 6 months from randomisation | 
| Congenital malformations | Any visible external congenital abnormality on surface examination | 6 months from randomisation | 
| Maternal mortality | 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. | 8 months from randomisation | 
| Other SAEs and AEs | Incidence of AEs and SAEs | 8 months from randomisation | 
| (History of) vomiting study drug | Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit | 6 months from randomisation | 
| Dizziness | Prevalence of dizziness after a course of IP | 6 months from randomisation | 
| Gastrointestinal complaints | Prevalence of gastrointestinal complaints after a course of IP | 6 months from randomisation | 
| 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 | 6 months from randomisation | 
| 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 | 6 months from randomisation | 
| Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples | Prevalence and incidence of carriage of macrolide resistant pneumococcus at randomization and delivery | 6 months from randomisation | 
| 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 | 6 months from randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IPTp, Malaria in Pregnancy, Intermittent Preventive Treatment