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Chloroquine for Malaria in Pregnancy

Primary Purpose

Malaria

Status
Completed
Phase
Phase 3
Locations
Malawi
Study Type
Interventional
Intervention
Chloroquine
Sulfadoxine-pyrimethamine
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Malaria focused on measuring malaria,Malawi,pregnancy

Eligibility Criteria

undefined - 99 Years (Child, Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Blantyre Malaria Project - Queen Elizabeth Central Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Chloroquine IPT

Chloroquine Prophylaxis

SP IPT

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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).
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.

Full Information

First Posted
September 1, 2011
Last Updated
November 3, 2016
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01443130
Brief Title
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

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria
Keywords
malaria,Malawi,pregnancy

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
900 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chloroquine IPT
Arm Type
Experimental
Arm Description
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.
Arm Title
Chloroquine Prophylaxis
Arm Type
Experimental
Arm Description
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.
Arm Title
SP IPT
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Chloroquine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sulfadoxine-pyrimethamine
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of Placental Malaria Infection Based on Histology
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Secondary Outcome Measure Information:
Title
Incidence of Placental Malaria by Placental Impression Smear
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Maternal Anemia (Hemoglobin < 10 Grams/Deciliter)
Description
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).
Time Frame
From enrollment until delivery, approximately 12-36 weeks
Title
Incidence of Maternal Severe Anemia (Hemoglobin < 7gm/dl)
Description
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.
Time Frame
From enrollment until delivery, approximately 12-36 weeks
Title
Incidence of Stillbirth
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Miscarriage
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Preterm Delivery
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Infant Mortality Rate to 14 Weeks of Age
Description
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.
Time Frame
For 14 weeks after delivery.
Title
Incidence of Low Birth Weight (LBW) (Birthweight < 2500 Grams)
Description
Maternal participants were followed to outcome of the pregnancy. The outcome measure provides the incidence of infants whose birthweight was less than 2500 grams.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Intrauterine Growth Restriction (IUGR)
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Active Placental Malaria Infection
Description
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).
Time Frame
At delivery: Approximately 12-36 weeks after enrollment
Title
Incidence of Malaria Infection, All Species.
Description
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.
Time Frame
Enrollment to delivery (approximately 12-36 weeks)
Title
Incidence of Clinical Malaria, All Species
Description
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.
Time Frame
Enrollment to delivery (approximately 12-36 weeks)
Title
Incidence of Infection in the Fetal Circulation
Description
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.
Time Frame
At delivery: Approximately 12-36 weeks after enrollment

10. Eligibility

Sex
Female
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
Blantyre Malaria Project - Queen Elizabeth Central Hospital
City
Blantryre
State/Province
Blantyre
Country
Malawi

12. IPD Sharing Statement

Citations:
PubMed Identifier
35057743
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.
Results Reference
derived
PubMed Identifier
35045119
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.
Results Reference
derived
PubMed Identifier
30195996
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. Erratum In: Lancet Infect Dis. 2019 Feb;19(2):e39.
Results Reference
derived

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Chloroquine for Malaria in Pregnancy

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