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Gestational Sulfadoxine-pyrimethamine and Azithromycin Treatment to Prevent Preterm Birth

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00131235
Recruitment Status : Active, not recruiting
First Posted : August 17, 2005
Last Update Posted : January 2, 2020
Sponsor:
Collaborators:
Academy of Finland
Foundation for Paediatric Research, Finland
Information provided by (Responsible Party):
Per Ashorn, Tampere University

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.

Condition or disease Intervention/treatment Phase
Malaria Sexually Transmitted Diseases Preterm Birth Pregnancy Drug: Sulfadoxine-pyrimethamine treatment twice during pregnancy Drug: Sulfadoxine-pyrimethamine at 4-week intervals Drug: Sulfadoxine-pyrimethamine every 4 weeks + azithromycin twice Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
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 Start Date : December 2003
Actual Primary Completion Date : June 2007
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Placebo Comparator: Control
Standard antenatal care as described in 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.

Other Name: Control

Experimental: Monthly SP
Standard antenatal care + monthly intermittent presumptive treatment of malaria with sulfadoxine pyrimethamine, as described in intervention
Drug: 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.

Other Name: Monthly SP

Experimental: AZI-SP
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

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.

Other Name: Azi-SP




Primary Outcome Measures :
  1. Proportion of preterm births [ Time Frame: once, after delivery ]
    Proportion of babies who are born before 37 completed gestation weeks

  2. Number of serious adverse events [ Time Frame: Cumulative during pregnancy and neonatal period ]
    Death, life-threatening event, hospitalization, congenital anomaly, or any othe condition consedered an SAE by a study physician


Secondary Outcome Measures :
  1. Percentage of low birth weight babies [ Time Frame: Once, after delivery ]
    Birth weight < 2500 g

  2. Mean birth weight [ Time Frame: Once, after delivery ]
    Measured in grams

  3. Mean duration of gestation [ Time Frame: Once, after delivery ]
    Measured in gestation weeks, expressed to one deciman,

  4. Percentage of low head circumference at birth [ Time Frame: Once, after delivery ]
    Below 2 standard deviations of the mean of international reference population

  5. Incidence of moderate underweight during infancy or childhood [ Time Frame: Cumulative during infancy and childhood ]
    weight for age Z-score < -2

  6. Perinatal mortality [ Time Frame: Cumulative until 7 days of post-natal life ]
    Stillbirths after 22 gestation weeks or within first 7 days of life / 1000 live births

  7. Neonatal mortality [ Time Frame: Cumulative until 28 days of post-natal life ]
    Deaths within first 28 days of life / 1000 live births

  8. Infant mortality [ Time Frame: Cumulative until 365 days of post-natal life ]
    Deaths within first 265 days of life / 1000 live births

  9. Mean maternal blood haemoglobin concentration at each antenatal visit and at 1, 3, and 6 months after delivery [ Time Frame: Several antenatal and postnatal visits ]
    Measured with hemocue meter, expressed as grams / liter

  10. Percentage of women with mild, moderate or severe anaemia at every antenatal visit and at 1, 3, and 6 months after delivery [ Time Frame: Several antenatal and postnatal visits ]
    Cut-offs for mild, moderate and severa anaemia 110 g / l - 80 g / l - 50 g / l

  11. Percentage of women with peripheral blood malaria parasitaemia at 32 gestational weeks and at delivery [ Time Frame: At enrolment, every 4 weeks thereafter and at delivery ]
    Measured with microscopy from fresh blood slides and with real-time PCR from dried blood spots

  12. Maternal weight gain during pregnancy [ Time Frame: Cumulative during pregnancy ]
    grams / gestation week

  13. Mean number of maternal illness days during pregnancy [ Time Frame: Cumulative during pregnancy ]
    Self reported illness symptoms

  14. Prevalence of maternal chlamydia trachomatis, neisseria gonorrhoea, and vaginal trichomoniasis infection at 4 weeks after delivery [ Time Frame: At 4 weeks after delivery ]
    Chlamydia and gonorhoea measured from urine samples with a PCR, vaginal trichomoniasis measures with a wet microscopy

  15. Attained lenght / height [ Time Frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age ]
    Measured as length until 2 years of age, then height; expressed in cm (one decimal) and as length / heigh for age Z-score

  16. Attained weight [ Time Frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age ]
    Expressed in kg with two decimals and as weight for age Z-score

  17. Nutritional status [ Time Frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age ]
    Mid-upper arm circumference, in mm (no decimals)

  18. Attained head circumference [ Time Frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age ]
    Head circumference, in mm, no decimals

  19. Childhood mortality, % of subjects who have died by the 10-12 year follow-up visit [ Time Frame: Cumulative incidence by 10-12 years of age ]
    Deaths, information obtained from parents or other adults who have lived in the same household with the child

  20. Motor development, Griffiths test, sub-score [ Time Frame: 5 years of age ]
    Summary score from questions in the gross motor and fine motor domain questions

  21. Social development, Griffiths test, sub-score [ Time Frame: 5 years of age ]
    Summary score from questions in the social development domain questions

  22. Cognitive development, Raven's colour matrix, score [ Time Frame: 10-12 years of age ]
    Summary score from 36 questions in the Raven's colour matrix test

  23. Reaction time, milliseconds [ Time Frame: 10-12 years of age ]

    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.


  24. Systolic blood pressure, mmHg [ Time Frame: 10-12 years of age ]
    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.

  25. Diastolic blood pressure, mmHg [ Time Frame: 10-12 years of age ]
    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.

  26. Central blood pressure, mmHg [ Time Frame: 10-12 years of age ]
    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.

  27. Pulse rate, beats / minutes [ Time Frame: 10-12 years of age ]
    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.

  28. Vascular resistance, mmHg·min/l [ Time Frame: 10-12 years of age ]
    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.

  29. Lean body mass, expressed in kg, with one decimal [ Time Frame: 10-12 years of age ]
    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)

  30. Fat mass, expressed in kg, with one decimal [ Time Frame: 10-12 years of age ]
    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)

  31. Fat percentage, expressed proportion of body weight (per cent, with one decimal) [ Time Frame: 10-12 years of age ]
    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)

  32. Self-rated well-being, score [ Time Frame: 10-12 years of age ]
    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.



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00131235


Locations
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Malawi
College of Medicine, University of Malawi
Mangochi, Mangochi District, Malawi
Sponsors and Collaborators
Tampere University
Academy of Finland
Foundation for Paediatric Research, Finland
Investigators
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Study Director: Per Ashorn, MD, PhD Tampere University, Faculty of Medicine and Health Technology
Principal Investigator: Kenneth M Maleta, MBBS, PhD University of Malawi College of Medicine
Additional Information:
Publications of Results:

Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Per Ashorn, Professor of Pediatrics, Tampere University
ClinicalTrials.gov Identifier: NCT00131235    
Other Study ID Numbers: SA-179787-1
First Posted: August 17, 2005    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: December 2019
Keywords provided by Per Ashorn, Tampere University:
Malaria
STI
Pregnancy
Prevention
Preterm birth
Low birth weight
Sub-Saharan Africa
Additional relevant MeSH terms:
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Sexually Transmitted Diseases
Malaria
Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Protozoan Infections
Parasitic Diseases
Infection
Virus Diseases
Genital Diseases, Male
Genital Diseases, Female
Azithromycin
Pyrimethamine
Sulfadoxine
Fanasil, pyrimethamine drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents