Clinical trial NCT00131235: Gestational Sulfadoxine-pyrimethamine and Azithromycin Treatment to Prevent Preterm Birth
Official title: Lungwena Antenatal Intervention Study. A Single-centre Intervention Trial in Rural Malawi, Testing Maternal and Infant Health Effects of Presumptive Intermittent Treatment of Pregnant Women With Sulfadoxine-pyrimethamine and Azithromycin
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Malaria
Sexually Transmitted Diseases
Preterm Birth
Pregnancy
Keywords: Malaria
STI
Pregnancy
Prevention
Preterm birth
Low birth weight
Sub-Saharan Africa
Lead sponsor: Tampere University
Sponsor class: OTHER
Collaborators: name: Academy of Finland
name: Foundation for Paediatric Research, Finland
First posted: 2005-08-17
Enrollment: 1320
Sex: FEMALE
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to examine whether treatment of pregnant Malawian women with repeated doses of sulfadoxine-pyrimethamine and azithromycin antibiotics will prevent preterm deliveries and result in other health benefits both for the mother and the foetus/newborn.

Detailed description: Maternal anaemia, preterm deliveries and low birth weight are common in Sub-Saharan Africa and contribute significantly to the ill-health of pregnant women and infants. The present study is based on the assumption that these adverse outcomes can be prevented by improved antimicrobial management of malaria and sexually transmitted infections (STI) among pregnant women. To test the hypothesis, a randomised clinical trial following Good Clinical Practice (GCP) is being carried out in Malawi, South-Eastern Africa.

A total of 1320 consenting women who present at a rural antenatal clinic after 14 but before 26 completed gestation weeks will be enrolled. One third of the women will receive antenatal care according to national recommendations, including regular visits to health centre, screening for pregnancy complications, haematinic and vitamin A supplementation and two doses of presumptive malaria treatment with sulfadoxine-pyrimethamine. Another third will receive otherwise the same care, but sulfadoxine-pyrimethamine treatment is given at monthly intervals. The final third receives standard antenatal care, sulfadoxine-pyrimethamine treatment at monthly intervals and two doses of presumptive STI treatment with azithromycin. Women are monitored throughout pregnancy and delivery and newborn growth will be followed up for five years.

The primary outcome measure is proportion of preterm births in the three study groups. Secondary maternal outcomes include anaemia and malaria parasitaemia during pregnancy, at delivery and at 1, 3, and 6 months after delivery, gestational weight gain and morbidity and STI prevalence after delivery. Secondary child outcomes consist of proportion of babies with low birth weight, mean birth weight, growth in infancy and childhood, incidence of malnutrition in infancy and childhood, and mortality. Additionally, information is collected on the development of malaria-specific humoral immunity in pregnancy and participant experiences from the study. Participant safety is systematically monitored throughout the intervention.

There have been two edits two the trial protocol, since the original approval. In the first one, there was an amendment to follow child growth and mortality until and child development at 5 years of age, with visits at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, and 60 months. In the second amendment, there was an addition to monitor child antropometrics, physical, mental, and social health at and mortality by 10-12 years of age.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* Age \>= 15 years
* Ultrasound confirmed pregnancy
* Quickening
* Foetal age 14-26 gestation weeks
* Maternal availability for follow-up during the entire study period

Exclusion Criteria:

* Known maternal tuberculosis, diabetes, kidney disease or liver disease
* Any severe acute illness warranting hospital referral at enrollment visit
* Mental disorder that may affect comprehension of the study or success of follow-up
* Twin pregnancy
* Pregnancy complications evident at enrollment visit (moderate to severe oedema, blood hemoglobin \[Hb\] concentration \< 50 g/l, systolic blood pressure \[BP\] \> 160 mmHg or diastolic BP \> 100 mmHg)
* Prior receipt of azithromycin during this pregnancy
* Receipt of sulfadoxine and pyrimethamine within 28 days of enrollment
* Known allergy to drugs containing sulfonamides, macrolides or pyrimethamine
* History of anaphylaxis
* History of any serious allergic reaction to any substance, requiring emergency medical care
* Concurrent participation in any other clinical trial

Primary outcomes:
measure: Proportion of preterm births
timeFrame: once, after delivery
measure: Number of serious adverse events
timeFrame: Cumulative during pregnancy and neonatal period
Secondary outcomes:
measure: Percentage of low birth weight babies
timeFrame: Once, after delivery
measure: Mean birth weight
timeFrame: Once, after delivery
measure: Mean duration of gestation
timeFrame: Once, after delivery
measure: Percentage of low head circumference at birth
timeFrame: Once, after delivery
measure: Incidence of moderate underweight during infancy or childhood
timeFrame: Cumulative during infancy and childhood
measure: Perinatal mortality
timeFrame: Cumulative until 7 days of post-natal life
measure: Neonatal mortality
timeFrame: Cumulative until 28 days of post-natal life
measure: Infant mortality
timeFrame: Cumulative until 365 days of post-natal life
measure: Mean maternal blood haemoglobin concentration at each antenatal visit and at 1, 3, and 6 months after delivery
timeFrame: Several antenatal and postnatal visits
measure: Percentage of women with mild, moderate or severe anaemia at every antenatal visit and at 1, 3, and 6 months after delivery
timeFrame: Several antenatal and postnatal visits
measure: Percentage of women with peripheral blood malaria parasitaemia at 32 gestational weeks and at delivery
timeFrame: At enrolment, every 4 weeks thereafter and at delivery
measure: Maternal weight gain during pregnancy
timeFrame: Cumulative during pregnancy
measure: Mean number of maternal illness days during pregnancy
timeFrame: Cumulative during pregnancy
measure: Prevalence of maternal chlamydia trachomatis, neisseria gonorrhoea, and vaginal trichomoniasis infection at 4 weeks after delivery
timeFrame: At 4 weeks after delivery
measure: Attained lenght / height
timeFrame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
measure: Attained weight
timeFrame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
measure: Nutritional status
timeFrame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
measure: Attained head circumference
timeFrame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
measure: Childhood mortality, % of subjects who have died by the 10-12 year follow-up visit
timeFrame: Cumulative incidence by 10-12 years of age
measure: Motor development, Griffiths test, sub-score
timeFrame: 5 years of age
measure: Social development, Griffiths test, sub-score
timeFrame: 5 years of age
measure: Cognitive development, Raven's colour matrix, score
timeFrame: 10-12 years of age
measure: Reaction time, milliseconds
timeFrame: 10-12 years of age
measure: Systolic blood pressure, mmHg
timeFrame: 10-12 years of age
measure: Diastolic blood pressure, mmHg
timeFrame: 10-12 years of age
measure: Central blood pressure, mmHg
timeFrame: 10-12 years of age
measure: Pulse rate, beats / minutes
timeFrame: 10-12 years of age
measure: Vascular resistance, mmHg·min/l
timeFrame: 10-12 years of age
measure: Lean body mass, expressed in kg, with one decimal
timeFrame: 10-12 years of age
measure: Fat mass, expressed in kg, with one decimal
timeFrame: 10-12 years of age
measure: Fat percentage, expressed proportion of body weight (per cent, with one decimal)
timeFrame: 10-12 years of age
measure: Self-rated well-being, score
timeFrame: 10-12 years of age
Other outcomes:
Locations:
city: Mangochi
country: Malawi
facility: College of Medicine, University of Malawi
state: Mangochi District
Study officials:
affiliation: Tampere University, Faculty of Medicine and Health Technology
name: Per Ashorn, MD, PhD
role: STUDY_DIRECTOR
affiliation: Kamuzu University of Health Sciences
name: Kenneth M Maleta, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A, MacArthur JR, Luntamo M, Ashorn P, Doumbo OK, ter Kuile FO. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis. JAMA. 2013 Feb 13;309(6):594-604. doi: 10.1001/jama.2012.216231.
citation: Hallamaa L, Cheung YB, Maleta K, Luntamo M, Ashorn U, Gladstone M, Kulmala T, Mangani C, Ashorn P. Child Health Outcomes After Presumptive Infection Treatment in Pregnant Women: A Randomized Trial. Pediatrics. 2018 Mar;141(3):e20172459. doi: 10.1542/peds.2017-2459.
citation: Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial. Am J Trop Med Hyg. 2010 Dec;83(6):1212-20. doi: 10.4269/ajtmh.2010.10-0264.
citation: Rantala AM, Taylor SM, Trottman PA, Luntamo M, Mbewe B, Maleta K, Kulmala T, Ashorn P, Meshnick SR. Comparison of real-time PCR and microscopy for malaria parasite detection in Malawian pregnant women. Malar J. 2010 Oct 6;9:269. doi: 10.1186/1475-2875-9-269.
citation: Aitken EH, Mbewe B, Luntamo M, Kulmala T, Beeson JG, Ashorn P, Rogerson SJ. Antibody to P. falciparum in pregnancy varies with intermittent preventive treatment regime and bed net use. PLoS One. 2012;7(1):e29874. doi: 10.1371/journal.pone.0029874. Epub 2012 Jan 27.
citation: Aitken EH, Mbewe B, Luntamo M, Maleta K, Kulmala T, Friso MJ, Fowkes FJ, Beeson JG, Ashorn P, Rogerson SJ. Antibodies to chondroitin sulfate A-binding infected erythrocytes: dynamics and protection during pregnancy in women receiving intermittent preventive treatment. J Infect Dis. 2010 May 1;201(9):1316-25. doi: 10.1086/651578.
citation: Luntamo M, Kulmala T, Cheung YB, Maleta K, Ashorn P. The effect of antenatal monthly sulphadoxine-pyrimethamine, alone or with azithromycin, on foetal and neonatal growth faltering in Malawi: a randomised controlled trial. Trop Med Int Health. 2013 Apr;18(4):386-97. doi: 10.1111/tmi.12074. Epub 2013 Feb 22.
citation: Xu J, Luntamo M, Kulmala T, Ashorn P, Cheung YB. A longitudinal study of weight gain in pregnancy in Malawi: unconditional and conditional standards. Am J Clin Nutr. 2014 Feb;99(2):296-301. doi: 10.3945/ajcn.113.074120. Epub 2013 Nov 13.
citation: Lin JT, Mbewe B, Taylor SM, Luntamo M, Meshnick SR, Ashorn P. Increased prevalence of dhfr and dhps mutants at delivery in Malawian pregnant women receiving intermittent preventive treatment for malaria. Trop Med Int Health. 2013 Feb;18(2):175-8. doi: 10.1111/tmi.12028. Epub 2012 Nov 30.
citation: Videman K, Hallamaa L, Heimonen O, Mangani C, Luntamo M, Maleta K, Ashorn P, Ashorn U. Child growth and neurodevelopment after maternal antenatal antibiotic treatment. Arch Dis Child. 2022 Apr;107(4):323-328. doi: 10.1136/archdischild-2021-322043. Epub 2021 Sep 3.
citation: Luntamo M, Rantala AM, Meshnick SR, Cheung YB, Kulmala T, Maleta K, Ashorn P. The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial. PLoS One. 2012;7(7):e41123. doi: 10.1371/journal.pone.0041123. Epub 2012 Jul 19.