Gestational Sulfadoxine-pyrimethamine and Azithromycin Treatment to Prevent Preterm Birth

Pregnancy Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00131235
• Other study ID #: SA-179787-1
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 2003
• Est. completion date: December 31, 2025

Study information

• Verified date: November 2023
• Source: Tampere University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1320
• Est. completion date: December 31, 2025
• Est. primary completion date: June 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 15 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malaria
• Pregnancy
• Premature Birth
• Preterm Birth
• Sexually Transmitted Diseases

Intervention

Drug:
• Sulfadoxine-pyrimethamine treatment twice during pregnancy
Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks. 2 placebo tablets for azithromycin taken at the same time points.
• Sulfadoxine-pyrimethamine at 4-week intervals
Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and then at 4 week intervals until 37.0 gestation weeks. 2 placebo tablets for azithromycin taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks.
• Sulfadoxine-pyrimethamine every 4 weeks + azithromycin twice
Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and then at 4 week intervals until 37.0 gestation weeks. 2 azithromycin tablets (each 500 mg) taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks.

Locations

Country	Name	City	State
Malawi	College of Medicine, University of Malawi	Mangochi	Mangochi District

Sponsors (3)

Lead Sponsor	Collaborator
Tampere University	Academy of Finland, Foundation for Paediatric Research, Finland

Country where clinical trial is conducted

Malawi, 

References & Publications (9)

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 20 — View 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 preventi — View 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. — View 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. — View 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. — View 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 — View 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):12 — View 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: 10.1186/1475-2875-9-2 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of preterm births	Proportion of babies who are born before 37 completed gestation weeks	once, after delivery
Primary	Number of serious adverse events	Death, life-threatening event, hospitalization, congenital anomaly, or any othe condition consedered an SAE by a study physician	Cumulative during pregnancy and neonatal period
Secondary	Percentage of low birth weight babies	Birth weight < 2500 g	Once, after delivery
Secondary	Mean birth weight	Measured in grams	Once, after delivery
Secondary	Mean duration of gestation	Measured in gestation weeks, expressed to one deciman,	Once, after delivery
Secondary	Percentage of low head circumference at birth	Below 2 standard deviations of the mean of international reference population	Once, after delivery
Secondary	Incidence of moderate underweight during infancy or childhood	weight for age Z-score < -2	Cumulative during infancy and childhood
Secondary	Perinatal mortality	Stillbirths after 22 gestation weeks or within first 7 days of life / 1000 live births	Cumulative until 7 days of post-natal life
Secondary	Neonatal mortality	Deaths within first 28 days of life / 1000 live births	Cumulative until 28 days of post-natal life
Secondary	Infant mortality	Deaths within first 265 days of life / 1000 live births	Cumulative until 365 days of post-natal life
Secondary	Mean maternal blood haemoglobin concentration at each antenatal visit and at 1, 3, and 6 months after delivery	Measured with hemocue meter, expressed as grams / liter	Several antenatal and postnatal visits
Secondary	Percentage of women with mild, moderate or severe anaemia at every antenatal visit and at 1, 3, and 6 months after delivery	Cut-offs for mild, moderate and severa anaemia 110 g / l - 80 g / l - 50 g / l	Several antenatal and postnatal visits
Secondary	Percentage of women with peripheral blood malaria parasitaemia at 32 gestational weeks and at delivery	Measured with microscopy from fresh blood slides and with real-time PCR from dried blood spots	At enrolment, every 4 weeks thereafter and at delivery
Secondary	Maternal weight gain during pregnancy	grams / gestation week	Cumulative during pregnancy
Secondary	Mean number of maternal illness days during pregnancy	Self reported illness symptoms	Cumulative during pregnancy
Secondary	Prevalence of maternal chlamydia trachomatis, neisseria gonorrhoea, and vaginal trichomoniasis infection at 4 weeks after delivery	Chlamydia and gonorhoea measured from urine samples with a PCR, vaginal trichomoniasis measures with a wet microscopy	At 4 weeks after delivery
Secondary	Attained lenght / height	Measured as length until 2 years of age, then height; expressed in cm (one decimal) and as length / heigh for age Z-score	1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Secondary	Attained weight	Expressed in kg with two decimals and as weight for age Z-score	1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Secondary	Nutritional status	Mid-upper arm circumference, in mm (no decimals)	1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Secondary	Attained head circumference	Head circumference, in mm, no decimals	1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Secondary	Childhood mortality, % of subjects who have died by the 10-12 year follow-up visit	Deaths, information obtained from parents or other adults who have lived in the same household with the child	Cumulative incidence by 10-12 years of age
Secondary	Motor development, Griffiths test, sub-score	Summary score from questions in the gross motor and fine motor domain questions	5 years of age
Secondary	Social development, Griffiths test, sub-score	Summary score from questions in the social development domain questions	5 years of age
Secondary	Cognitive development, Raven's colour matrix, score	Summary score from 36 questions in the Raven's colour matrix test	10-12 years of age
Secondary	Reaction time, milliseconds	This will be tested with an eye-tracking device (Tobii). Participants are asked to look from the fixation point to different directions or fixate the gaze at one point. We will measure the horizontal eye-movements (saccades) and calculate the reaction times, scoring the task correct/incorrect (direction).; This eye-tracking system is based on a Pupil Centre Corneal Reflection (PCCR) technique, in which near infrared illumination is reflected on the cornea relative to the center of the pupil. The eye-tracking cameras capture the light reflections and create a 3D model of the eye and head-position to track the participant's point of gaze at high temporal and spatial accuracy (60 Hz/0.4°). The results will be stored automatically into a data base.	10-12 years of age
Secondary	Systolic blood pressure, mmHg	Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.	10-12 years of age
Secondary	Diastolic blood pressure, mmHg	Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.	10-12 years of age
Secondary	Central blood pressure, mmHg	Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.	10-12 years of age
Secondary	Pulse rate, beats / minutes	Will use oscillometric Mobil o Graph blood pressure monitoring system. We will measure pulse rate / minutes, when the child is first sitting, then standing and last lying down.	10-12 years of age
Secondary	Vascular resistance, mmHg·min/l	Will use oscillometric Mobil o Graph blood pressure monitoring system. We will measure vascular resistance, when the child is first sitting, then standing and last lying down.	10-12 years of age
Secondary	Lean body mass, expressed in kg, with one decimal	Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)	10-12 years of age
Secondary	Fat mass, expressed in kg, with one decimal	Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)	10-12 years of age
Secondary	Fat percentage, expressed proportion of body weight (per cent, with one decimal)	Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)	10-12 years of age
Secondary	Self-rated well-being, score	Self-reported well-being will be measured with 11 question panel with rating from 1-5 expressed as smileys. The questions consider about "how happy you are about the things you own, school, house you live, food, clothes, other pupils, friends, the family, safety feeling, the way you look, with yourself". Score for self-reported well-being will be calculated as a sum of ratings for each item divided by the number of items with non-missing data. There are two items related to the child's school and they are not applicable if the child does not go to school. The minimum score for self-reported well-being is 1 and the maximum is 5, and the score will be expressed with one decimal.	10-12 years of age

External Links

•   Tampere Center for Child Health Research: Global Health Group home-page