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 endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617001494325
Ethics application status
Approved
Date submitted
12/09/2017
Date registered
23/10/2017
Date last updated
2/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The WHO ACTION-II (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) Trial: A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the late preterm period in hospitals in low-resource countries to improve newborn outcomes
Scientific title
WHO ACTION-II Trial - A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the late preterm period in hospitals in low-resource countries to improve newborn outcomes
Secondary ID [1] 292857 0
CTRI/2017/05/008721
Universal Trial Number (UTN)
Trial acronym
The WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) II Trial
Linked study record
ACTRN12617000476336

Health condition
Health condition(s) or problem(s) studied:
preterm birth 304697 0
Condition category
Condition code
Reproductive Health and Childbirth 304008 304008 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Antenatal corticosteroids (Dexamethasone IM)

The drug regimen for this trial is aligned with the WHO recommendations on use of antenatal corticosteroids. The intervention regimen will be:
- A single course of 6mg dexamethasone by intramuscular injection, administered every 12 hours, to a total of four (4) doses (time points 0 hours, 12 hours, 24 hours and 36 hours)
- If the full regimen is completed, the woman would have received a total of 24mg in divided doses

No repeat course(s) will be used.

Adherence will be monitored through documenting number of injections administered to each participant.
Intervention code [1] 299098 0
Treatment: Drugs
Comparator / control treatment
Identical placebo (normal saline), administered according to the same regimen as for dexamethasone, with one injection every 12 hours to a total of four doses.
Control group
Placebo

Outcomes
Primary outcome [1] 303339 0
Any baby death:
a. Neonatal death (death of a liveborn within 28 completed days of life)
b. Stillbirth or neonatal death (any death of a fetus (post enrollment), or death of a live birth within 28 completed days of life among all enrolled participants.
Timepoint [1] 303339 0
From randomization to 28 completed days of life
Primary outcome [2] 303340 0
Severe respiratory distress of neonate (based on clinical features and SpO2 level <90% or use of supplemental oxygen)
Timepoint [2] 303340 0
birth to 28 days of life (during initial postnatal hospitalization only)
Primary outcome [3] 303341 0
Possible maternal bacterial infection (Occurrence of maternal fever, or clinically suspected or confirmed infection, for which therapeutic antibiotics were used)
Timepoint [3] 303341 0
Randomization to 28 days postpartum (during hospital admission only)
Secondary outcome [1] 338674 0
Stillbirth
Timepoint [1] 338674 0
randomization to birth
Secondary outcome [2] 338675 0
Early neonatal death
Timepoint [2] 338675 0
birth to 7 completed days of life
Secondary outcome [3] 338676 0
Neonatal sepsis (clinical diagnosis, made by clinical assessment of neonatal care physician)
Timepoint [3] 338676 0
birth to 28 days of life (during initial postnatal hospitalization only)
Secondary outcome [4] 338677 0
Severe intraventricular haemorrhage (sIVH) (assessed using transcranial ultrasound at Day 7 of life or discharge, whichever comes first).
Timepoint [4] 338677 0
birth, up to 7 days of life or discharge (whichever comes first)
Secondary outcome [5] 338678 0
Neonatal hypoglycemia is defined as any blood glucose measure less than 45 mg/dl (2.6mmol/l)
Timepoint [5] 338678 0
birth to 28 days of life (during initial postnatal hospitalization only)
Secondary outcome [6] 338679 0
Apgar score: Apgar <7 at 5 minutes
Timepoint [6] 338679 0
first 5 minutes of life
Secondary outcome [7] 338680 0
Maternal death
Timepoint [7] 338680 0
randomization to 28 days postpartum
Secondary outcome [8] 338681 0
Maternal fever (greater than or equal to 38.0 C ) as measured using calibrated thermometer
Timepoint [8] 338681 0
Randomization to 28 days postpartum (during postpartum admission/s only)
Secondary outcome [9] 338682 0
Chorioamnionitis (suspected or confirmed), based on clinical assessment by obstetric care physician
Timepoint [9] 338682 0
Randomization to 28 days postpartum (during postpartum admission/s only)
Secondary outcome [10] 338683 0
Postpartum endometritis (suspected or confirmed), based on clinical assessment by obstetric care physician
Timepoint [10] 338683 0
Randomization to 28 days postpartum (during postpartum admission/s only)
Secondary outcome [11] 338684 0
Wound infection (suspected or confirmed), based on clinical assessment by obstetric care physician
Timepoint [11] 338684 0
Randomization to 28 days postpartum (during postpartum admission/s only)
Secondary outcome [12] 338685 0
Non-obstetric infection (suspected or confirmed), based on clinical assessment by obstetric care physician
Timepoint [12] 338685 0
Randomization to 28 days postpartum (during postpartum admission/s only)
Secondary outcome [13] 338686 0
Major neonatal resuscitation at birth (The use of positive pressure ventilation for more than one minute), assessed in medical record
Timepoint [13] 338686 0
immediate postnatal period
Secondary outcome [14] 338687 0
Timing of breast milk feeding initiation (Timing of initiation of breast milk feeding in hours after birth (breastfeeding, cup or tube feeding), assessed in medical record or maternal report.
Timepoint [14] 338687 0
birth to start of breast milk feeding (whichever comes first)
Secondary outcome [15] 338688 0
Timing to full enteral feeding, assessed in medical record.
Timepoint [15] 338688 0
birth to start of full enteral feeding (whichever comes first)
Secondary outcome [16] 338689 0
Use of oxygen therapy (reported as any use, and length of use in days) measured through use of medical records and direct observation of newborn.
Timepoint [16] 338689 0
birth to 28 days of life (during initial postnatal hospitalization only)
Secondary outcome [17] 338690 0
continuous positive airway pressure (CPAP) ventilation (reported as any use, length of use in days), measured through use of medical records and direct observation of newborn.
Timepoint [17] 338690 0
birth to 28 days of life (during initial postnatal hospitalization only)
Secondary outcome [18] 338691 0
Mechanical ventilation (MV) (reported as any use of MV during admission. and length of use in days) measured through use of medical records and direct observation of newborn. .
Timepoint [18] 338691 0
birth to 28 days of life (during initial postnatal hospitalization only)
Secondary outcome [19] 338692 0
Use of therapeutic antibiotics (intravenous or intramuscular) for 5 or more days (reported as any use and length of use) measured through use of medical records and direct observation of newborn.
Timepoint [19] 338692 0
birth to 28 days of life (during initial hospitalization only)
Secondary outcome [20] 338693 0
Surfactant treatment (reported as any use, and total number of doses) measured through use of medical records and direct observation of newborn
Timepoint [20] 338693 0
birth to 28 days of life (during initial hospitalization only)
Secondary outcome [21] 338694 0
Length of newborn's hospital stay after birth, measured through use of medical records
Timepoint [21] 338694 0
birth to 28 days of life (initial hospitalization only)
Secondary outcome [22] 338695 0
Admission of newborn to a special newborn care unit (SCU) (reported as any admission, length of admission), measured through use of medical records
Timepoint [22] 338695 0
birth to 28 days of life (during initial hospitalization only)
Secondary outcome [23] 338696 0
Newborn readmission for healthcare at facility (reported as any readmission, length of stay, number of readmissions, and cause of readmission) measured through use of medical records
Timepoint [23] 338696 0
birth to 28 days of life
Secondary outcome [24] 338697 0
Maternal therapeutic antibiotic use (reported as a any therapeutic antibiotic use, and number of days of therapeutic antibiotic use) measured through use of medical records
Timepoint [24] 338697 0
randomization to 28 days postpartum (during hospitalization only)
Secondary outcome [25] 338698 0
Any use of antibiotics in an enrolled participant (maternal) while in facility (prophylactic or therapeutic) measured through use of medical records
Timepoint [25] 338698 0
Randomization to 28 days postpartum (during hospitalization only)
Secondary outcome [26] 338699 0
Length of total maternal hospitalization for birth (days), measured through use of medical records
Timepoint [26] 338699 0
Randomization to 28 days postpartum (during hospitalization only)
Secondary outcome [27] 338700 0
Maternal readmission for healthcare at facility (reported as any readmission, length of stay, number of readmissions, and cause of readmission) measured through use of medical records
Timepoint [27] 338700 0
Randomization to 28 days postpartum (during hospitalization only)
Secondary outcome [28] 338701 0
Any maternal referral to another facility, measured through use of medical records
Timepoint [28] 338701 0
Randomization to 28 days postpartum (during hospitalization only)
Secondary outcome [29] 338702 0
Compliance with study allocation, through research assistants recording number of doses administered.
Timepoint [29] 338702 0
Randomization until birth
Secondary outcome [30] 338704 0
Total number of treatment or placebo doses received, through research assistants recording number of doses administered.
Timepoint [30] 338704 0
Randomization until birth
Secondary outcome [31] 338705 0
Time from initiation of first dose until birth, through research assistants recording number and timing of doses administered.
Timepoint [31] 338705 0
Randomization until birth
Secondary outcome [32] 338706 0
Gestational age at birth
Timepoint [32] 338706 0
birth

Eligibility
Key inclusion criteria
- Birth planned or expected within 48 hours
- Gestational age from 34 weeks 0 days to 36 weeks 0 days
- Women with singleton or multiple pregnancies, where the fetus(es) is(are) alive
- Women with no clinical signs of severe infection (as per clinical assessment)
- Women willing and able to provide consent (or if a minor, provides assent and guardian provides consent)
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Intrauterine fetal death
2. Major or lethal congenital fetal anomaly identified
3. Clinical suspicion or evidence of clinical chorioamnionitis, as per obstetric care physician assessment
4. Clinical suspicion or evidence of severe infection, as per obstetric care physician assessment
5. No prior ultrasound-based estimate of gestational age available and immediate ultrasound examination is not possible
6. Any concurrent or recent (within the past 2 weeks) systemic corticosteroid use during the current pregnancy (outside of trial)
7. Unwilling or unable to provide consent
8. Currently a participant in another clinical trial related to maternal and neonatal health
9. Any other clinical indication where the treating clinician considers corticosteroids to be contraindicated

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The assignment schedule will be stored at WHO. Allocation concealment will be achieved by having identical treatment packs (i.e. intervention and control are in identical packaging) assembled in containers delivered to study centres. At time of randomization, study staff will take the next sequentially numbered pack from the box. The container is designed to ensure that packs are taken sequentially.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence will be generated by the study data manager/programmer. The study statistician and WHO project manager will liaise with the study pack packaging company, to ensure that intervention and control packs are absolutely identical and their sequence is according to the randomization sequence. Boxes of study packs will be sent directly to participating centres.

Local investigators and research teams will conduct the allocation. Once eligibility is confirmed and consent obtained, the next sequentially numbered pack will be pulled by the research assistant from the box containing the study packs and administered according to
study procedures.

Participating centres will pilot study activities before commencement of screening and recruitment.

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Follow up of enrolled women and newborns to 28 days postpartum/postnatal
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Based on a superiority hypothesis, a total of 22,589 women are needed to detect a reduction of 15% or more in neonatal deaths, from 8.0% deaths to 6.8%, among neonates of women who received ACS at 34 to 36 weeks, in a two-sided 5% significance test with 90% power (including 10% loss to follow-up).

The primary analysis will be based on all participants with outcome data available. Any participants with protocol violations, including women who no longer wish to receive their allocated intervention but are prepared to have data collected, will be analyzed in the group to which they were allocated (‘intention- to-treat strategy’). We also plan to conduct a secondary “per-protocol” analysis. It is expected that few patients will cross over or be lost to follow up, hence it is expected that these two analyses will likely closely agree.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9191 0
India
State/province [1] 9191 0
Country [2] 9192 0
Bangladesh
State/province [2] 9192 0
Country [3] 9193 0
Pakistan
State/province [3] 9193 0
Country [4] 9194 0
Nigeria
State/province [4] 9194 0
Country [5] 9195 0
Kenya
State/province [5] 9195 0

Funding & Sponsors
Funding source category [1] 297488 0
Charities/Societies/Foundations
Name [1] 297488 0
Bill and Melinda Gates Foundation
Address [1] 297488 0
500 Fifth Avenue North
Seattle, WA 98109
Country [1] 297488 0
United States of America
Primary sponsor type
Other
Name
World Health Organization
Address
20 Avenue Appia, Geneva, Switzerland 1211
Country
Switzerland
Secondary sponsor category [1] 296487 0
University
Name [1] 296487 0
International Center for Maternal and Newborn Health
Address [1] 296487 0
International Center for Maternal and Newborn Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
Country [1] 296487 0
United States of America
Secondary sponsor category [2] 296488 0
University
Name [2] 296488 0
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Address [2] 296488 0
Departments of Obstetrics & Gynaecology and Neonatology
Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh
Country [2] 296488 0
Bangladesh
Secondary sponsor category [3] 296489 0
University
Name [3] 296489 0
KLE University’s Jawaharlal Nehru Medical College
Address [3] 296489 0
KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India
Country [3] 296489 0
India
Secondary sponsor category [4] 296490 0
University
Name [4] 296490 0
Kenyatta National Hospital
Address [4] 296490 0
Kenyatta National Hospital, Hospital Road,Upper Hill, Nairobi 00202, Kenya
Country [4] 296490 0
Kenya
Secondary sponsor category [5] 296491 0
University
Name [5] 296491 0
University of Nairobi, Nairobi, Kenya
Address [5] 296491 0
Department of Obstetrics and Gynaecology and Department of Paediatrics, University of Nairobi, P. O. Box 19676-00202, Kenyatta National Hospital, Nairobi Kenya
Country [5] 296491 0
Kenya
Secondary sponsor category [6] 296492 0
University
Name [6] 296492 0
University of Ibadan
Address [6] 296492 0
Departments of Paediatrics and Obstetrics & Gynaecology, College of Medicine, University of Ibadan, Ibadan, Nigeria
Country [6] 296492 0
Nigeria
Secondary sponsor category [7] 296493 0
University
Name [7] 296493 0
Obafemi Awolowo University
Address [7] 296493 0
Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
Country [7] 296493 0
Nigeria
Secondary sponsor category [8] 296494 0
University
Name [8] 296494 0
Aga Khan University
Address [8] 296494 0
Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan
Country [8] 296494 0
Pakistan
Other collaborator category [1] 279713 0
Individual
Name [1] 279713 0
Professor Abdullah H. Baqui
Address [1] 279713 0
International Center for Maternal and Newborn Health, Johns Hopkins Bloomberg School of Public Health
Country [1] 279713 0
United States of America
Other collaborator category [2] 279714 0
Individual
Name [2] 279714 0
Saleha Begum Chowdhury
Address [2] 279714 0
Department of Obstetrics & Gynaecology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Country [2] 279714 0
Bangladesh
Other collaborator category [3] 279715 0
Individual
Name [3] 279715 0
Mohammod Shahidullah
Address [3] 279715 0
Department of Neonatology, Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh
Country [3] 279715 0
Bangladesh
Other collaborator category [4] 279716 0
Individual
Name [4] 279716 0
Shivaprasad Goudar
Address [4] 279716 0
Women’s and Children’s Health Research Unit, KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India
Country [4] 279716 0
India
Other collaborator category [5] 279717 0
Individual
Name [5] 279717 0
Sangappa M Dhaded
Address [5] 279717 0
KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India
Country [5] 279717 0
India
Other collaborator category [6] 279718 0
Individual
Name [6] 279718 0
John Kinuthia
Address [6] 279718 0
Department of Research & Programs, Kenyatta National Hospital, Nairobi, Kenya
Country [6] 279718 0
Kenya
Other collaborator category [7] 279719 0
Individual
Name [7] 279719 0
Zahida Qureshi
Address [7] 279719 0
Department of Obstetrics and Gynaecology, School of Medicine, University of Nairobi, Nairobi, Kenya
Country [7] 279719 0
Kenya
Other collaborator category [8] 279720 0
Individual
Name [8] 279720 0
Frederick Were
Address [8] 279720 0
University of Nairobi, Nairobi, Kenya
Country [8] 279720 0
Kenya
Other collaborator category [9] 279721 0
Individual
Name [9] 279721 0
Adejumoke Idowu Ayede
Address [9] 279721 0
Department of Paediatrics, College of Medicine, University of Ibadan, Ibadan, Nigeria
Country [9] 279721 0
Nigeria
Other collaborator category [10] 279722 0
Individual
Name [10] 279722 0
Bukola Fawole
Address [10] 279722 0
Department of Obstetrics & Gynaecology, College of Medicine, University of Ibadan, Ibadan, Nigeria
Country [10] 279722 0
Nigeria
Other collaborator category [11] 279723 0
Individual
Name [11] 279723 0
Ebunoluwa A. Adejuyigbe
Address [11] 279723 0
Faculty of Medicine, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
Country [11] 279723 0
Nigeria
Other collaborator category [12] 279724 0
Individual
Name [12] 279724 0
Oluwafemi Kuti
Address [12] 279724 0
Department of Obstetrics, Gynaecology and Perinatology, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
Country [12] 279724 0
Nigeria
Other collaborator category [13] 279725 0
Individual
Name [13] 279725 0
Shabina Ariff
Address [13] 279725 0
Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan
Country [13] 279725 0
Pakistan

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298589 0
WHO Ethics Review Committee
Ethics committee address [1] 298589 0
World Health Organization
20 Avenue Appia
Geneva, Switzerland, 1211
Ethics committee country [1] 298589 0
Switzerland
Date submitted for ethics approval [1] 298589 0
27/03/2017
Approval date [1] 298589 0
14/06/2017
Ethics approval number [1] 298589 0
ERC 0002905

Summary
Brief summary
The aim of this trial is to determine whether antenatal corticosteroids are safe and efficacious for women and newborns in resource-limited settings, when given to women with a live fetus/es at risk of imminent preterm birth from 34 weeks 0 days to 36 weeks 0 days gestation in facilities for the prevention of neonatal deaths.
Trial website
Trial related presentations / publications
Public notes
WHO ACTION-II Trial Principal investigators:
Bangladesh site - Professor Abdullah H. Baqui, Dr Saleha Begum Chowdhury, Professor Mohammod Shahidullah
India site - Professor Shivaprasad Goudar, Professor Sangappa M Dhaded, Dr John Kinuthia
Kenya site - Professor Zahida Qureshi, Professor Frederick Were,
Nigeria (Ibadan site) - Dr Adejumoke Idowu Ayede, Dr Bukola Fawole,
Nigeria (Ile-Ife site) - Professor Ebunoluwa A. Adejuyigbe, Professor Oluwafemi Kuti
Pakistan site - Dr Shabina Ariff

WHO project co-ordinators: Dr Rajiv Bahl & Dr A. Metin Gülmezoglu
WHO project managers: Dr Olufemi T. Oladapo & Dr Joshua P. Vogel

Contacts
Principal investigator
Name 77578 0
Dr A. Metin Gulmezoglu
Address 77578 0
Department of Reproductive Health and Research
World Health Organization
20 Avenue Appia
Geneva
Switzerland, 1211
Country 77578 0
Switzerland
Phone 77578 0
+41227913417
Fax 77578 0
Email 77578 0
gulmezoglum@who.int
Contact person for public queries
Name 77579 0
Dr A. Metin Gulmezoglu
Address 77579 0
Department of Reproductive Health and Research
World Health Organization
20 Avenue Appia
Geneva
Switzerland, 1211
Country 77579 0
Switzerland
Phone 77579 0
+41227913417
Fax 77579 0
Email 77579 0
gulmezoglum@who.int
Contact person for scientific queries
Name 77580 0
Dr A. Metin Gulmezoglu
Address 77580 0
Department of Reproductive Health and Research
World Health Organization
20 Avenue Appia
Geneva
Switzerland, 1211
Country 77580 0
Switzerland
Phone 77580 0
+41227913417
Fax 77580 0
Email 77580 0
gulmezoglum@who.int

No information has been provided regarding IPD availability
Summary results
No Results