Gestational Sulfadoxine-pyrimethamine and Azithromycin Treatment to Prevent Preterm Birth

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Preterm Birth, Pregnancy, Malaria, Sexually Transmitted Diseases

Intervention / Treatment
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* Drug: Sulfadoxine-pyrimethamine treatment twice during pregnancy
* Drug: Sulfadoxine-pyrimethamine at 4-week intervals
* Drug: Sulfadoxine-pyrimethamine every 4 weeks + azithromycin twice


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Standard antenatal care as described in intervention | Drug: Sulfadoxine-pyrimethamine treatment twice during pregnancy<br>* 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.<br>* Other names: Control;|
| Experimental: Monthly SP<br>Standard antenatal care + monthly intermittent presumptive treatment of malaria with sulfadoxine pyrimethamine, as described in intervention | Drug: Sulfadoxine-pyrimethamine at 4-week intervals<br>* 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.<br>* Other names: Monthly SP;|
| Experimental: AZI-SP<br>Standard antenatal care + monthly intermittent presumptive treatment of malaria with sulfadoxine pyrimethamine + two presumptive treatments of sexually transmitted infections and malaria with azithromycin, as described in intervention | Drug: Sulfadoxine-pyrimethamine every 4 weeks + azithromycin twice<br>* 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.<br>* Other names: Azi-SP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of preterm births | Proportion of babies who are born before 37 completed gestation weeks | once, after delivery | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of low birth weight babies | Birth weight < 2500 g | Once, after delivery | 
| Mean birth weight | Measured in grams | Once, after delivery | 
| Mean duration of gestation | Measured in gestation weeks, expressed to one deciman, | Once, after delivery | 
| Percentage of low head circumference at birth | Below 2 standard deviations of the mean of international reference population | Once, after delivery | 
| Incidence of moderate underweight during infancy or childhood | weight for age Z-score < -2 | Cumulative during infancy and childhood | 
| 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 | 
| Neonatal mortality | Deaths within first 28 days of life / 1000 live births | Cumulative until 28 days of post-natal life | 
| Infant mortality | Deaths within first 265 days of life / 1000 live births | Cumulative until 365 days of post-natal life | 
| 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 | 
| 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 | 
| 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 | 
| Maternal weight gain during pregnancy | grams / gestation week | Cumulative during pregnancy | 
| Mean number of maternal illness days during pregnancy | Self reported illness symptoms | Cumulative during pregnancy | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Motor development, Griffiths test, sub-score | Summary score from questions in the gross motor and fine motor domain questions | 5 years of age | 
| Social development, Griffiths test, sub-score | Summary score from questions in the social development domain questions | 5 years of age | 
| Cognitive development, Raven's colour matrix, score | Summary score from 36 questions in the Raven's colour matrix test | 10-12 years of age | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, STI, Pregnancy, Prevention, Preterm birth, Low birth weight, Sub-Saharan Africa