Chloroquine for Malaria in Pregnancy

Study Overview
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Brief Summary
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The purpose of this study is to test prevention strategies for pregnancy-related malaria. Researchers will compare different malaria treatments and treatment schedules which include chloroquine therapy (weekly doses versus being dosed twice during pregnancy for 3 days each time) to the standard practice of preventive treatment intervals in pregnancy (with the drug sulfadoxine-pyrimethamine given twice during pregnancy). Participants will include 900 pregnant women, who will be assigned to one of three treatment groups. Blood samples will be collected at every visit before birth and any time the participant is ill to determine if malaria is present. Pregnant women will be monitored during pregnancy and newborns will be assessed at birth and followed until about 14 weeks. Participant involvement in the study is expected to last about 12 months.

Detailed Description
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In areas of high malaria endemicity, typical of much of sub-Saharan Africa, despite having achieved semi-immunity to malaria in adulthood, women become vulnerable to malaria infection during pregnancy, especially during their first or second pregnancy. They have increased rates of infection in the peripheral blood and high concentrations of parasites can be found in the placenta. On histological examination, mature asexual parasites, forms that are not usually detected in the peripheral blood, accumulate in the placenta. Pregnancy-specific variant surface antigens are responsible for the increased vulnerability of pregnant women to malaria because they are unrecognized by the immune systems of women who encounter them for the first time in their first pregnancy. In subsequent pregnancies, women develop immunity to these parasite surface antigens and the parasites are cleared by the host response. Plasmodium (P) falciparum infection during pregnancy has important health consequences for both pregnant women and their newborns. Adverse outcomes of pregnancy-associated malaria that have been documented in Malawi include maternal anemia, low birth weight (LBW), and increased infant mortality. The primary objective of the study is to compare weekly chloroquine prophylaxis and chloroquine intermittent preventative therapy (IPT) for malaria in pregnancy (IPTp) to the standard practice [IPTp with sulfadoxine-pyrimethamine (SP)] with respect to prevention of placental malaria. The secondary objectives are: to compare weekly chloroquine prophylaxis and chloroquine IPTp to the standard practice (IPTp with SP) with respect to prevention of malaria during pregnancy; to compare weekly chloroquine prophylaxis and chloroquine IPTp to the standard practice (IPTp with SP) with respect to prevention of the adverse maternal and newborn effects of pregnancy-associated malaria. The exploratory objective identify the vulnerable periods during pregnancy when malaria infection is more likely to cause placental infection, maternal anemia, and low infant birth weight. This is a randomized controlled trial to compare chloroquine as IPT or chloroquine as chemoprophylaxis to IPTp with SP. Women will be randomized after Screening and enrollment, and they begin the assigned treatment between Week 20 and Week 28 gestation. Specimens will be collected at every prenatal visit and any time the participant is ill to determine if malaria is present. Pregnant women will be monitored during pregnancy, and newborns will be assessed at birth and followed until they are approximately 14 weeks of age. Participants will be randomized to one of the following regimens: Chloroquine approximately 1,500 mg base over 3 days, twice during pregnancy (2 tablets on Day 0, 2 tablets on Day 1, 1 tablet on Day 2); Chloroquine base 600 mg (2 tablets) loading dose followed by 300 mg (1 tablet) orally once per week until delivery; SP 1500 mg/75 mg twice during pregnancy.

Official Title
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A Randomized, Controlled Clinical Trial of Chloroquine as Chemoprophylaxis Versus Intermittent Preventive Therapy to Prevent Malaria in Pregnancy in Malawi

Conditions
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Malaria

Intervention / Treatment
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* Drug: Chloroquine
* Drug: Sulfadoxine-pyrimethamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who present to the Ndirande Antenatal Clinic (ANC) and meet the following inclusion criteria will be enrolled in the study: -Before the end of 27th week of gestation -First or second pregnancy -Anticipate remaining in Blantyre until 14 weeks after delivery -Agree to deliver at the Ndirande Health Centre or Queen Elizabeth Central Hospital (QECH) -Provision of informed consent Exclusion Criteria: -Chronic use (>14 days) of any medication with antimalarial or antifolate activity -Human immunodeficiency virus (HIV) infection -Known high-risk pregnancy requiring regular supervision of an obstetrician -Allergy to any of the study drugs

Ages Eligible for Study
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Maximum Age: 99 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

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 |
| --- | --- |
| Experimental: Chloroquine IPT<br>300 subjects to receive a therapeutic dose of chloroquine (1,500 mg given over 3 days, 2 tablets on Day 0, 2 tablets on Day 1, 1 tablet on Day 2) will be administered twice during pregnancy at 20-28 weeks and at 28-34 weeks. | Drug: Chloroquine<br>* Chloroquine tablets contain 300 mg chloroquine base per tablet. Dosages: Chloroquine 1,500 mg base over 3 days twice during pregnancy or Chloroquine 600 mg loading dose followed by 300 mg orally once per week. Intermittant preventative treatment in pregnancy (IPTp) doses will be administered between weeks 20-28 and weeks 28-34 gestation, 4 weeks apart. Participants randomized to IPTp with chloroquine will require their second and third doses of chloroquine after the initial dose given in the clinic and those assigned to chloroquine chemoprophylaxis will require weekly doses.<br>|
| Experimental: Chloroquine Prophylaxis<br>300 subjects to receive a loading dose of chloroquine (base) 600 mg (2 tablets) at first administration followed by 300 mg of chloroquine base (1 tablet) every week. | Drug: Chloroquine<br>* Chloroquine tablets contain 300 mg chloroquine base per tablet. Dosages: Chloroquine 1,500 mg base over 3 days twice during pregnancy or Chloroquine 600 mg loading dose followed by 300 mg orally once per week. Intermittant preventative treatment in pregnancy (IPTp) doses will be administered between weeks 20-28 and weeks 28-34 gestation, 4 weeks apart. Participants randomized to IPTp with chloroquine will require their second and third doses of chloroquine after the initial dose given in the clinic and those assigned to chloroquine chemoprophylaxis will require weekly doses.<br>|
| Active Comparator: SP IPT<br>300 subjects to receive a therapeutic dose of sulfadoxine-pyrimethamine (SP), (1500 mg sulfadoxine and 75 mg pyrimethamine (3 tablets)) administered twice during pregnancy at 20-28 weeks and at 28-34 weeks. | Drug: Sulfadoxine-pyrimethamine<br>* Sulfadoxine-pyrimethamine 3 tablets (1,500 mg sulfadoxine and 75 mg pyrimethamine) twice during pregnancy. Intermittant preventive treatment in pregnancy (IPTp) doses will be administered between weeks 20-28 and weeks 28-34, 4 weeks apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Placental Malaria Infection Based on Histology | The placenta was collected at the time of delivery for examination by histology to determine malaria infection. Malaria infection was concluded if histology identified parasites or malaria pigment in the placental tissue. | At delivery: Approximately 12-36 weeks after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Placental Malaria by Placental Impression Smear | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of malaria infection in the placenta based on diagnosis by positive placental impression smear results. | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Maternal Anemia (Hemoglobin < 10 Grams/Deciliter) | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of anemia among maternal participants during pregnancy . Anemia is defined as having a hemoglobin value less than 10 grams/deciliter (gm/dL). | From enrollment until delivery, approximately 12-36 weeks | 
| Incidence of Maternal Severe Anemia (Hemoglobin < 7gm/dl) | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of severe anemia among maternal participants during pregnancy. Severe anemia is defined as having a hemoglobin value less than 7 gm/dl. | From enrollment until delivery, approximately 12-36 weeks | 
| Incidence of Stillbirth | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of participants' deliveries whose outcome was stillbirth, defined as an infant born without any signs of life at 28 weeks or greater of gestation. | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Miscarriage | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of participants' deliveries whose outcome was miscarriage, defined as an infant delivered without any signs of life at less than 28 weeks of gestation. | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Preterm Delivery | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of participants' deliveries whose outcome was preterm delivery, defined as delivery less than 37 weeks of gestation. The outcome of the delivery was not considered, and could have been live birth, stillbirth, or miscarriage. | At delivery: Approximately 12-36 weeks after enrollment | 
| Infant Mortality Rate to 14 Weeks of Age | Infants were followed from the time of delivery until 14 weeks of age. This outcome measure provides the incidence of infants who died within 14 weeks of delivery. | For 14 weeks after delivery. | 
| Incidence of Low Birth Weight (LBW) (Birthweight < 2500 Grams) | Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of infants whose birthweight was less than 2500 grams. | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Intrauterine Growth Restriction (IUGR) | Infants were followed from the time of delivery until 14 weeks of age. This outcome measure provides the incidence of infants with IUGR at delivery. IUGR is defined as weight below the 10th percentile for gestational age based on the World Health Organization (WHO) fetal growth curve. This classification is supported by literature resulting from the INTERGROWTH-21st Project; José Villar. | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Active Placental Malaria Infection | Maternal participants were followed to outcome of the pregnancy. This outcome measure provides the number of placental malaria infections in maternal subjects diagnosed by the presence of parasites and/or pigment on histological section or molecular evidence of infection (PCR). | At delivery: Approximately 12-36 weeks after enrollment | 
| Incidence of Malaria Infection, All Species. | Maternal participants were followed to outcome of the pregnancy. This outcome measure provides the number of malaria infection episodes measured by positive parasitemia in maternal subjects. | Enrollment to delivery (approximately 12-36 weeks) | 
| Incidence of Clinical Malaria, All Species | Maternal participants were followed to outcome of the pregnancy. Clinical malaria is defined as malaria infection at any parasite density with associated symptoms including at least one of the following: objective fever measured at the clinic, history of fever in the past 48 hours or other symptoms in the last 48 hours including: headache, myalgia, vomiting, or weakness. | Enrollment to delivery (approximately 12-36 weeks) | 
| Incidence of Infection in the Fetal Circulation | Maternal participants were followed to outcome of the pregnancy. This outcome measure provides the number of positive for malaria cord blood smear and cord PCR results in maternal subjects based on the results of the thick smear and PCR from the cord blood sample. | At delivery: Approximately 12-36 weeks after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria,Malawi,pregnancy