Clinical trial NCT01443130: Chloroquine for Malaria in Pregnancy
Official title: A Randomized, Controlled Clinical Trial of Chloroquine as Chemoprophylaxis Versus Intermittent Preventive Therapy to Prevent Malaria in Pregnancy in Malawi
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: malaria,Malawi,pregnancy
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2011-09-29
Enrollment: 900
Sex: FEMALE
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Placental Malaria Infection Based on Histology
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
Secondary outcomes:
measure: Incidence of Placental Malaria by Placental Impression Smear
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Maternal Anemia (Hemoglobin < 10 Grams/Deciliter)
timeFrame: From enrollment until delivery, approximately 12-36 weeks
measure: Incidence of Maternal Severe Anemia (Hemoglobin < 7gm/dl)
timeFrame: From enrollment until delivery, approximately 12-36 weeks
measure: Incidence of Stillbirth
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Miscarriage
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Preterm Delivery
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Infant Mortality Rate to 14 Weeks of Age
timeFrame: For 14 weeks after delivery.
measure: Incidence of Low Birth Weight (LBW) (Birthweight < 2500 Grams)
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Intrauterine Growth Restriction (IUGR)
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Active Placental Malaria Infection
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
measure: Incidence of Malaria Infection, All Species.
timeFrame: Enrollment to delivery (approximately 12-36 weeks)
measure: Incidence of Clinical Malaria, All Species
timeFrame: Enrollment to delivery (approximately 12-36 weeks)
measure: Incidence of Infection in the Fetal Circulation
timeFrame: At delivery: Approximately 12-36 weeks after enrollment
Other outcomes:
Locations:
city: Blantryre
country: Malawi
facility: Blantyre Malaria Project - Queen Elizabeth Central Hospital
state: Blantyre
Study officials:
References:
citation: Patson N, Mukaka M, Kazembe L, Eijkemans MJC, Mathanga D, Laufer MK, Chirwa T. Comparison of statistical methods for the analysis of recurrent adverse events in the presence of non-proportional hazards and unobserved heterogeneity: a simulation study. BMC Med Res Methodol. 2022 Jan 20;22(1):24. doi: 10.1186/s12874-021-01475-8.
citation: Patson N, Mukaka M, Peterson I, Divala T, Kazembe L, Mathanga D, Laufer MK, Chirwa T. Effect of adverse events on non-adherence and study non-completion in malaria chemoprevention during pregnancy trial: A nested case control study. PLoS One. 2022 Jan 19;17(1):e0262797. doi: 10.1371/journal.pone.0262797. eCollection 2022.
citation: Divala TH, Mungwira RG, Mawindo PM, Nyirenda OM, Kanjala M, Ndaferankhande M, Tsirizani LE, Masonga R, Muwalo F, Boudova S, Potter GE, Kennedy J, Goswami J, Wylie BJ, Muehlenbachs A, Ndovie L, Mvula P, Mbilizi Y, Tomoka T, Laufer MK. Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial. Lancet Infect Dis. 2018 Oct;18(10):1097-1107. doi: 10.1016/S1473-3099(18)30415-8. Epub 2018 Sep 5.