ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12617000476336

Ethics application status

Approved

Date submitted

3/02/2017

Date registered

31/03/2017

Date last updated

22/03/2021

Date data sharing statement initially provided

22/03/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

The WHO ACTION-I (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 early preterm period in hospitals in low-resource countries to improve newborn outcomes

Scientific title

WHO ACTION-I 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 early preterm period in hospitals in low-resource countries to improve newborn outcomes

Secondary ID [1]

A65913

Universal Trial Number (UTN)

Trial acronym

The WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) I Trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

preterm birth

Condition category

Condition code

Reproductive Health and Childbirth

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
- If a woman has not delivered within 7 completed days after completion of the first course, is re-assessed as eligible (if the gestational age is still less than 34 weeks), and a subsequent clinical assessment demonstrates that birth is planned or expected in the next 48 hours, a second course according to the regimen described above will be administered. Hence, the use of a repeat course in eligible women shall be the same as the initial allocation (i.e. women initially randomized to dexamethasone will only receive dexamethasone as repeat course).

No further repeat courses will be used (i.e. a maximum of two courses per participant).

Adherence will be monitored through documenting number of injections administered to each participant.

Intervention code [1]

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.

- If a woman has not delivered within 7 completed days after completion of the first course, is re-assessed as eligible (if the gestational age is still less than 34 weeks), and a subsequent clinical assessment demonstrates that birth is planned or expected in the next 48 hours, a second course according to the regimen described above will be administered.

Control group

Placebo

Outcomes

Primary outcome [1]

Neonatal death

Timepoint [1]

birth to 28 completed days of life

Primary outcome [2]

Stillbirth or neonatal death

Timepoint [2]

Any death of a fetus (post enrolment) or death of a live birth, from randomization to 28 completed days of life

Primary outcome [3]

Possible maternal bacterial infection (Occurrence of maternal fever, or clinically suspected or confirmed infection, for which therapeutic antibiotics were used)

Timepoint [3]

Randomization to 28 days postpartum (during hospital admission only)

Secondary outcome [1]

Stillbirth

Timepoint [1]

randomization to birth

Secondary outcome [2]

Early neonatal death

Timepoint [2]

birth to 7 completed days of life

Secondary outcome [3]

Severe respiratory distress of neonate (based on clinical features and SpO2 level <90% or use of supplemental oxygen) (overall; and at 24 hours)

Timepoint [3]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [4]

Neonatal sepsis (clinical diagnosis, made by clinical assessment of neonatal care physician)

Timepoint [4]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [5]

Severe intraventricular haemorrhage (sIVH) (assessed using transcranial ultrasound at Day 7 of life or discharge, whichever comes first).

Timepoint [5]

birth, up to 7 days of life or discharge (whichever comes first)

Secondary outcome [6]

Neonatal hypoglycemia is defined as blood glucose measure less than 45 mg/dl (2.6mmol/l) (overall, and at 6 and 36 hours)

Timepoint [6]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [7]

Apgar score <7 at 5 minutes

Timepoint [7]

first 5 minutes of life

Secondary outcome [8]

Maternal death

Timepoint [8]

randomization to 28 days postpartum

Secondary outcome [9]

Maternal fever (greater than or equal to 38.0 C ) as measured using calibrated thermometer

Timepoint [9]

Randomization to 28 days postpartum (during hospital admission/s only)

Secondary outcome [10]

Chorioamnionitis (suspected or confirmed), based on clinical assessment by obstetric care physician

Timepoint [10]

Randomization to birth

Secondary outcome [11]

Postpartum endometritis (suspected or confirmed), based on clinical assessment by obstetric care physician

Timepoint [11]

Randomization to 28 days postpartum (during postpartum admission/s only)

Secondary outcome [12]

Wound infection (suspected or confirmed), based on clinical assessment by obstetric care physician

Timepoint [12]

Randomization to 28 days postpartum (during postpartum admission/s only)

Secondary outcome [13]

Non-obstetric infection (suspected or confirmed), based on clinical assessment by obstetric care physician

Timepoint [13]

Randomization to 28 days postpartum (during hospital admission/s only)

Secondary outcome [14]

Major neonatal resuscitation at birth (The use of positive pressure ventilation for more than one minute), assessed in medical record

Timepoint [14]

immediate postnatal period

Secondary outcome [15]

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 [15]

birth to start of breast milk feeding (whichever comes first)

Secondary outcome [16]

Timing to full enteral feeding, assessed in medical record.

Timepoint [16]

birth to start of full enteral feeding (whichever comes first)

Secondary outcome [17]

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 [17]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [18]

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 [18]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [19]

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 [19]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [20]

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 [20]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [21]

Surfactant treatment (reported as any use, and total number of doses) measured through use of medical records and direct observation of newborn

Timepoint [21]

during initial postnatal hospitalization only, until death, discharge or completed 7 days (whichever comes first)

Secondary outcome [22]

Length of newborn's hospital stay after birth, measured through use of medical records

Timepoint [22]

birth to 28 days of life (initial hospitalization only)

Secondary outcome [23]

Admission of newborn to a special newborn care unit (SCU) (reported as any admission, length of admission), measured through use of medical records

Timepoint [23]

birth to 28 days of life (during initial hospitalization only)

Secondary outcome [24]

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 [24]

birth to 28 days of life

Secondary outcome [25]

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 [25]

randomization to 28 days postpartum (during hospitalization only)

Secondary outcome [26]

Any use of antibiotics in an enrolled participant (maternal) while in facility (prophylactic or therapeutic) measured through use of medical records

Timepoint [26]

Randomization to 28 days postpartum (during hospitalization only)

Secondary outcome [27]

Length of total maternal hospitalization for birth (days), measured through use of medical records

Timepoint [27]

Randomization to 28 days postpartum (during hospitalization only)

Secondary outcome [28]

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 [28]

Randomization to 28 days postpartum (during hospitalization only)

Secondary outcome [29]

Any maternal referral to another facility, measured through use of medical records

Timepoint [29]

Randomization to 28 days postpartum (during hospitalization only)

Secondary outcome [30]

Compliance with study allocation, through research assistants recording number of doses administered.

Timepoint [30]

Randomization until birth

Secondary outcome [31]

Use of repeat course (treatment or placebo), through research assistants recording number of doses administered.

Timepoint [31]

Randomization until birth

Secondary outcome [32]

Total number of treatment (dexamethasone or placebo) doses received, through research assistants recording number of doses administered.

Timepoint [32]

Randomization until birth

Secondary outcome [33]

Time from initiation of first dose until birth, through research assistants recording number and timing of doses administered.

Timepoint [33]

Randomization until birth

Eligibility

Key inclusion criteria

- Birth planned or expected within 48 hours
- Gestational age from 26 weeks 0 days to 33 weeks 6 days (see Figure 3)
- 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

Sex

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.

In this trial, some women will be randomized and complete the assigned course, but will not deliver. When they re-present to the facility, they will be re-assessed for eligibility for a repeat course. This repeat treatment will be according to the initial allocation. Blinding will be ensured, while maintaining the initial allocation.

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

A total of about 5,416 women are needed to detect a reduction of 15% or more from a 25% deaths to 21.3%, among neonates from women who were administered ACS at <34 weeks, in a two-sided 5% significant test with 90% power. With 10% loss to follow-up, about 6,018 women will have to be recruited.

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

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Other reasons/comments

Other reasons

DSMB recommended the trial be stopped early for benefit.

Date of first participant enrolment

Anticipated

1/06/2017

Actual

24/12/2017

Date of last participant enrolment

Anticipated

1/06/2019

Actual

21/11/2019

Date of last data collection

Anticipated

28/06/2019

Actual

20/02/2020

Sample size

Target

6018

Accrual to date

Final

2852

Recruitment outside Australia

Country [1]

India

State/province [1]

Country [2]

Bangladesh

State/province [2]

Country [3]

Pakistan

State/province [3]

Country [4]

Nigeria

State/province [4]

Country [5]

Kenya

State/province [5]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Bill and Melinda Gates Foundation

Address [1]

500 Fifth Avenue North
Seattle, WA 98109

Country [1]

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]

University

Name [1]

International Center for Maternal and Newborn Health

Address [1]

International Center for Maternal and Newborn Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA

Country [1]

United States of America

Secondary sponsor category [2]

University

Name [2]

Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Address [2]

Departments of Obstetrics & Gynaecology and Neonatology
Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh

Country [2]

Bangladesh

Secondary sponsor category [3]

University

Name [3]

KLE University’s Jawaharlal Nehru Medical College

Address [3]

KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India

Country [3]

India

Secondary sponsor category [4]

University

Name [4]

Kenyatta National Hospital

Address [4]

Kenyatta National Hospital, Hospital Road,Upper Hill, Nairobi 00202, Kenya

Country [4]

Kenya

Secondary sponsor category [5]

University

Name [5]

University of Nairobi, Nairobi, Kenya

Address [5]

Department of Obstetrics and Gynaecology and Department of Paediatrics, University of Nairobi, P. O. Box 19676-00202, Kenyatta National Hospital, Nairobi Kenya

Country [5]

Kenya

Secondary sponsor category [6]

University

Name [6]

University of Ibadan

Address [6]

Departments of Paediatrics and Obstetrics & Gynaecology, College of Medicine, University of Ibadan, Ibadan, Nigeria

Country [6]

Nigeria

Secondary sponsor category [7]

University

Name [7]

Obafemi Awolowo University

Address [7]

Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria

Country [7]

Nigeria

Secondary sponsor category [8]

University

Name [8]

Aga Khan University

Address [8]

Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan

Country [8]

Pakistan

Other collaborator category [1]

Individual

Name [1]

Professor Abdullah H. Baqui

Address [1]

International Center for Maternal and Newborn Health, Johns Hopkins Bloomberg School of Public Health

Country [1]

United States of America

Other collaborator category [2]

Individual

Name [2]

Saleha Begum Chowdhury

Address [2]

Department of Obstetrics & Gynaecology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Country [2]

Bangladesh

Other collaborator category [3]

Individual

Name [3]

Mohammod Shahidullah

Address [3]

Department of Neonatology, Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh

Country [3]

Bangladesh

Other collaborator category [4]

Individual

Name [4]

Shivaprasad Goudar

Address [4]

Women’s and Children’s Health Research Unit, KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India

Country [4]

India

Other collaborator category [5]

Individual

Name [5]

Sangappa M Dhaded

Address [5]

KLE University’s Jawaharlal Nehru Medical College, Belgaum 590010 Karnataka India

Country [5]

India

Other collaborator category [6]

Individual

Name [6]

John Kinuthia

Address [6]

Department of Research & Programs, Kenyatta National Hospital, Nairobi, Kenya

Country [6]

Kenya

Other collaborator category [7]

Individual

Name [7]

Zahida Qureshi

Address [7]

Department of Obstetrics and Gynaecology, School of Medicine, University of Nairobi, Nairobi, Kenya

Country [7]

Kenya

Other collaborator category [8]

Individual

Name [8]

Frederick Were

Address [8]

University of Nairobi, Nairobi, Kenya

Country [8]

Kenya

Other collaborator category [9]

Individual

Name [9]

Adejumoke Idowu Ayede

Address [9]

Department of Paediatrics, College of Medicine, University of Ibadan, Ibadan, Nigeria

Country [9]

Nigeria

Other collaborator category [10]

Individual

Name [10]

Bukola Fawole

Address [10]

Department of Obstetrics & Gynaecology, College of Medicine, University of Ibadan, Ibadan, Nigeria

Country [10]

Nigeria

Other collaborator category [11]

Individual

Name [11]

Ebunoluwa A. Adejuyigbe

Address [11]

Faculty of Medicine, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria

Country [11]

Nigeria

Other collaborator category [12]

Individual

Name [12]

Oluwafemi Kuti

Address [12]

Department of Obstetrics, Gynaecology and Perinatology, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria

Country [12]

Nigeria

Other collaborator category [13]

Individual

Name [13]

Shabina Ariff

Address [13]

Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan

Country [13]

Pakistan

Other collaborator category [14]

Individual

Name [14]

Olubukola Adeponle Adesina

Address [14]

University of Ibadan and University College Hospital, Ibadan, Nigeria

Country [14]

Nigeria

Other collaborator category [15]

Individual

Name [15]

Lumaan Sheikh

Address [15]

Aga Khan University, Karachi, Pakistan

Country [15]

Pakistan

Other collaborator category [16]

Individual

Name [16]

Sajid Soofi

Address [16]

Aga Khan University, Karachi, Pakistan

Country [16]

Pakistan

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WHO Ethics Review Committee

Ethics committee address [1]

World Health Organization
20 Avenue Appia
Geneva, Switzerland, 1211

Ethics committee country [1]

Switzerland

Date submitted for ethics approval [1]

14/12/2016

Approval date [1]

20/02/2017

Ethics approval number [1]

ERC 0002851

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 26 weeks 0 days  to 33 weeks 6 days gestation in facilities for the prevention of neonatal deaths.

Trial website

Trial related presentations / publications

Public notes

WHO ACTION-I 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 Olubukola Adeponle Adesina 
Nigeria (Ile-Ife site) - Professor Ebunoluwa A. Adejuyigbe, Professor Oluwafemi Kuti
Pakistan site - Dr Shabina Ariff, Dr Lumaan Sheikh, Dr Sajid Soofi

Trial Co-ordinating Unit: 
Maternal – Olufemi T. Oladapo, Joshua P. Vogel, Fernando Althabe (from 2019), A. Metin Gulmezoglu (2015-2019); 
Newborn – Rajiv Bahl, Suman Rao (from 2019), Ayesha De Costa (from 2019), Shuchita Gupta (from 2019); Statistician – Gilda Piaggio; WHO Data Manager – My Huong Nguyen

Contacts

Principal investigator

Name

Dr Olufemi T. Oladapo

Address

Department of Sexual and Reproductive Health and Research World Health Organization 20 Avenue Appia Geneva Switzerland, 1211

Country

Switzerland

Phone

+41227914226

Fax

[email protected]

Contact person for public queries

Name

Olufemi T. Oladapo

Address

Department of Sexual and Reproductive Health and Research World Health Organization 20 Avenue Appia Geneva Switzerland, 1211

Country

Switzerland

Phone

+41227914226

Fax

[email protected]

Contact person for scientific queries

Name

Olufemi T. Oladapo

Address

Department of Sexual and Reproductive Health and Research World Health Organization 20 Avenue Appia Geneva Switzerland, 1211

Country

Switzerland

Phone

+41227914226

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
11116	Study protocol		https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3488-z
11117	Informed consent form		https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3488-z

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial: A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries.	2019	https://dx.doi.org/10.1186/s13063-019-3488-z
Embase	Antenatal dexamethasone for early preterm birth in low-resource countries.	2020	https://dx.doi.org/10.1056/NEJMoa2022398

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically