Efficacy and Safety of IPTp-DP Versus IPTp-SP in Malawi

Study Overview
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Brief Summary
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This study aims to compare the efficacy of monthly IPTp-DP with monthly IPTp-SP to determine if IPTp-DP is associated with a reduction in malaria infection at delivery among HIV-negative women in an area with high levels of SP resistance in Malawi.

Detailed Description
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Problem to be studied Malaria in pregnancy (MiP) due to Plasmodium falciparum infection is a major cause of maternal morbidity and poor birth outcomes in malaria-endemic countries. Pregnant women are at increased risk of more frequent and severe malaria infections than non-pregnant women. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), which involves administration of treatment doses of SP at each antenatal visit in the second and third trimesters of pregnancy, at least one month apart, irrespective of malaria parasitemia, is currently recommended for all women, except HIV positive women taking daily cotrimoxazole prophylaxis, in areas with stable moderate to high transmission of malaria. SP is the only drug currently used for IPTp. Due to increasing resistance to SP, it is no longer used as a treatment for symptomatic malaria, however, IPTp-SP remains effective even in areas where SP resistance in children under five (determined by in vivo efficacy studies) is up to 26%, and continues to be used for IPTp in countries where SP is no longer recommended to treat symptomatic malaria. However, IPTp-SP has become more controversial given recent data from northern Tanzania and Malawi that have demonstrated that at higher rates of resistance, IPTp-SP may no longer be effective. Alternative drugs which could replace SP have been tested; mefloquine, azithromycin-chloroquine, and amodiaquine have been abandoned as options due to poor tolerability among pregnant women. Dihydroartemisinin-Piperaquine (DP) remains an attractive option because of the long half-life of piperaquine (PQ) and the demonstrated efficacy, safety, and tolerability in pregnancy. Recent studies in Kenya and Uganda using DP for IPTp demonstrated a significant reduction in the prevalence of malaria throughout pregnancy and at the time of delivery. However, there was not a clear benefit in terms of improved neonatal outcomes. Additional studies are therefore needed to determine the impact of switching from IPTp-SP to IPTp-DP. Study aims Primary objectives To compare the efficacy of monthly IPTp-DP with monthly IPTp-SP to determine if IPTp-DP is associated with a reduction in malaria infection at delivery among HIV-negative women in an area with high levels of SP resistance in Malawi. Secondary objectives To determine if IPTp-DP results in decreased fetal morbidity compared with IPTp-SP, where fetal morbidity is defined as the composite of any of the following: Preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2,500 grams), or small for gestational age (SGA). To evaluate the tolerability and safety of IPTp-DP in the second and third trimesters of pregnancy, including an assessment of cardiac risk, as measured by changes in QTc intervals from baseline with each successive dose. To compare the frequency of adverse events and fetal congenital malformations in IPTp-DP with IPTp-SP. To assess how SP and DP affect the maternal intestinal and vaginal microbiome. Methodology Open-label, 2 arm randomized controlled superiority trial to compare the efficacy and safety of IPTp-DP to IPTp-SP in Malawi. The trial is designed to show a 60% decrease in malaria infection at delivery among HIV-negative women of all gravidity when IPTp-DP is used instead of IPTp-SP. Expected findings and dissemination It is expected that in areas of high SP resistance, IPTp-DP will be superior to IPTp-SP in decreasing malaria infection at delivery. In addition, it is anticipated that DP will be well-tolerated among pregnant women and that fetal outcomes will be better than IPTp-SP.

Official Title
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A Prospective Randomized Open-Label Study on the Efficacy and Safety of Intermittent Preventive Treatment in Pregnancy (IPTp) With Dihydroartemisinin-Piperaquine (DP) Versus IPTp With Sulfadoxine-Pyrimethamine (SP) in Malawi

Conditions
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Malaria, Pregnancy

Intervention / Treatment
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* Drug: Sulfadoxine-pyrimethamine
* Drug: dihydroartemisinin-piperaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Viable singleton pregnancy Gestational age ≤28 completed weeks (28 6/7) by fundal height/ultrasound Maternal age ≥16 years No history of IPTp use during this pregnancy Willing to participate and complete the study schedule, including laboratory studies and delivery in the labor ward of the study clinic or hospital Willing to sign or thumb print informed consent Resident of study area and intending to stay in the area for the duration of the follow-up HIV-negative at enrolment Exclusion Criteria: HIV-positive or unknown Multiple gestation High-risk pregnancy, including any pre-existing illness likely to cause complication of pregnancy (hypertension, diabetes, asthma, epilepsy, renal disease, liver disease, fistula repair, leg or spine deformity) Severe anemia requiring blood transfusion (Hb <7.0 g/dL) at enrolment Known allergy or previous adverse reaction to any of the study drugs Previous inclusion in the same study Participating in other malaria intervention studies Known or suspected cardiac disease Corrected QT interval (QTcF) greater than 450 ms at baseline Patients taking any of the following drugs: Antimicrobial agents of the following classes (systemic use only): Macrolides (e.g. erythromycin, clarithromycin, azithromycin, roxithromycin) Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin) Pentamidine Antiarrhythmic agents (e.g. amiodarone, sotalol) Antihistamines (e.g. promethazine) Antifungals (systemic): ketoconazole, fluconazole, itraconazole Antiretrovirals: Saquinavir Diuretics (e.g. hydrochlorothiazide, furosemide) Antipsychotics (neuroleptics): haloperidol, thioridazine Antidepressants: imipramine, citalopram, escitalopram Antiemetics: domperidone, chlorpromazine, ondansetron

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sulfadoxine-pyrimethamine<br>Intermittent preventive treatment with Sulfadoxine-pyrimethamine: Monthly dose of 3 co-formulated tablets containing 500 mg sulfadoxine and 25 mg pyrimethamine | Drug: Sulfadoxine-pyrimethamine<br>* 500 mg sulfadoxine and 25 mg pyrimethamine<br>* Other names: Fansidar;|
| Experimental: dihydroartemisinin-piperaquine<br>Intermittent preventive treatment with dihydroartemisinin-piperaquine: Monthly course of daily doses of co-formulated DP tablets containing 40 mg dihydroartemisinin and 320 mg piperaquine, dosed based on the woman's weight, for 3 days: 24-35.9 kg: Two tablets 36-59.9 kg: Three tablets 60-79.9 kg: Four tablets ≥80 kg: Five tablets | Drug: dihydroartemisinin-piperaquine<br>* 40 mg dihydroartemisinin and 320 mg piperaquine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Malaria infection at the time of delivery | The composite of peripheral and placental parasitemia, detected by placental histology, positive peripheral blood smear at the time of delivery, or positive rapid diagnostic test at the time of delivery | delivery | 
| Fetal morbidity | Composite endpoint of fetal morbidity, defined as any of the following: Preterm birth (birth before 37 weeks gestation), Low-birth-weight (birth weight under 2,500 grams), Small for gestational age (SGA) | Delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electrocardiogram changes following the receipt of DP | QTc will be measured in a subset of women 4-6 hours after the 3rd dose of each course | 4-6 hours after the 3rd dose with each course | 
| Microbiome changes following receipt of DP or SP | We will measure the changes in the intestinal and vaginal microbiome induced by DP and SP | From date of randomization until the date of delivery or last date of follow-up, average of  4-5 months | 
| Maternal hemoglobin at 3rd trimester |  | 3rd trimester | 
| Maternal anemia at 3rd trimester |  | 3rd trimester | 
| Fetal anemia | Anemia/ hemoglobin measured from cord blood | Delivery | 
| Incidence of clinical malaria episodes |  | From date of randomization until the date of delivery or last date of follow-up, average of  4-5 months | 
| Incidence of all cause sick visits |  | From date of randomization until the date of delivery or last date of follow-up, average of  4-5 months | 
| Serious adverse events |  | From date of randomization until the date of delivery or last date of follow-up, average of  4-5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Pregnancy, Malawi, Intermittent preventive treatment, dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine