1. What data in particular will be shared?
   Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
   


2. What additional supporting information will be shared?
   Response -  Study Protocol
   Response -  Statistical Analysis Plan
   Response - Informed Consent Form
   Response - Clinical Study Report
   
   
3. Who will be able to view these files?
   Response - Researchers whose proposed use of the data has been approved by an independent review committee identified for this purpose.
   


4. For what types of analyses will this data be available?
   Response - To achieve aims in the approved proposal.
   


5. By what mechanism will data be made available?
   Response (Others) -  By mail communication to Dr Yeshita V Pujar (yvpujar@hotmail.com), Dr Shivaprasad Goudar (sgoudar@jnmc.edu) and Dr Jyotsna Suri (drpratima@hotmail.com)


6. For how long will this data be available start date provided 01-01-2025 and end date provided 31-12-2029?
   Response - Beginning 3 months and ending 5 years following article publication.
   


7. Any URL or additional information regarding plan/policy for sharing IPD? 
   Additional Information - NIL

Burden of Preterm Birth 

Preterm birth is the single largest cause of neonatal death, and over 80% of all preterm births occur in low and middle-income countries. It is a major contributor to under five mortality. In spite of lower mortality/morbidity in late preterm compared to early preterm they contribute significantly because of larger number 

Antenatal Corticosteroids (ACS) in preterm birth 

The current standard of care is to administer antenatal corticosteroids (ACS) to women at risk of preterm birth prior to 34 weeks’ gestation. This is to accelerate fetal lung maturation and thus improve neonatal outcomes in the event of delivery. Recently completed ACTION-I trial showed benefit of ACS in early preterm (26-34 wks). Benefit of ACS in late preterm (34-36 weeks) is less clear 

Pharmacokinetics & Pharmacodynamics 

Recent animal studies have suggested that lung maturational changes can be effected at much lower doses of ACS than those conventionally used in clinical practice. As ACS is one of the most effective strategies available to reduce neonatal mortality and morbidity from preterm birth, it is critical to ascertain the PK/PD of ACS, to ensure that fetal exposure is optimal. WHO is currently conducting the ACTION-III trial, a multi-country trial recruiting 13,500 women at risk of late preterm birth, and randomizing them to one of three arms (This study is registered in CTRI with registration number: CTRI/2021/03/032429. The knowledge gained from PK/PD study of ACS can be used for future calibration of optimal ACS dosing in the light of their demonstrated efficacy in early preterm birth, and in the event that efficacy is also demonstrated for late preterm birth. 

Primary Objectives

• To study the population PK of betamethasone phosphate 2 mg IM administered every 12 hours and dexamethasone phosphate 6 mg IM administered every 12 hours in pregnant women at risk of late preterm birth.
• To study PD effects of betamethasone and dexamethasone in the above doses on pregnant women; and to compare these parameters to those in pregnant women who do not receive either betamethasone or dexamethasone.

Secondary Objectives

• To assess levels of dexamethasone phosphate and betamethasone phosphate in cord blood at birth and identify a fetal: maternal ratio of the drugs.
• To study PD parameters in cord blood of ACS-treated women and compare these parameters with those obtained from cord blood of placebo-treated women
• To compare the above (i-iv) in African (Nigerian) and South Asian (Indian) pregnant populations.

Study Design

• PK/PD study nested within a Phase III clinical trial (WHO ACTION-III trial), using sparse sampling approach

Study Sites 

This PK/PD study will be conducted at two Nigerian and two Indian sites recruiting for the ACTION III trial. These two countries are selected because of:

• Representativeness of women from the India and Nigeria sites to reflect the BMI of South Asian and West African pregnant women. 
• Ability of facilities to closely follow the protocol (particularly sample timing, processing and storage requirements) of this study at these sites 
• Ease of transportation of samples to India where the assay will be done. 

The following hospitals recruiting for the ACTION III trial will participate in this study:

• Safdarjung Hospital, New Delhi, India
• KLE Hospital, Belgavi, India
• University of Abuja hospital, Nigeria
• Ife University hospital Ife, Nigeria
• Island Maternity, Lagos, Nigeria
• University college hospital Ibadan, Nigeria

Study Population 

Consecutive women enrolled into the ACTION III trial will be approached over a period of 4 months. A subgroup of women enrolled into the three arms of the ACTION III trial will be invited to participate in the PK PD study. The three arms of the ACTION III trial include the following: 

Arm 1: Dexamethasone phosphate 6mg IM 12hrly for 4 doses 

Arm 2: Betamethasone phosphate 2mg IM 12hrly for 4 doses 

Arm 3: Saline placebo 

Inclusion Criteria 

A subgroup of women from each of the three arms of the ACTION III trial 

Exclusion Criteria 

ACTION III participants who are diabetic, severely anaemic or with features of HELLP syndrome will be excluded 

Blinding 

Blinded: Random IDs to be approached will be provided centrally (consecutive as far as possible – to facilitate logistics) 

Approach 

A population PK approach will be conducted to describe the PK of betamethasone and dexamethasone. Population PK modelling approaches rely on data from multiple individuals and often utilize pooled data from multiple patients, sampled at pragmatic intervals (sparse sampling). This approach is generally used to analyse clinical data collected in a setting where intense PK sampling are not practical, such as in Phase 3 trials, for ethical reasons (this method was used in determining dose of antiretrovirals in pregnancy) 

Sample collection 

Serial maternal venipuncture samples will be collected from prior to administration of the first dose of the study intervention, up to 2 hour after birth. Maximum of 5 draws per participant will be collected for the PK study. These same draws will also be used for the PD measures. An additional 2 samples on day 2 and day 3 will be drawn to allow the measure of PD parameters as they approach baseline. As far as possible, study draws will be combined with sample draws necessary for routine care to minimize stress and discomfort to the patient. 

Outcome 

Outcomes of interest include ACS levels and PD parameter levels (cortisol, glucose, white cell counts). One study form will be developed for data collection. This will be piloted in participating centers to identify any problems in form structure or content. Sample collection, processing, and measurement 

Plasma steroid concentration measurement

The plasma steroid levels will be assayed at central FDA approved facility in India. Dexamethasone and betamethasone will be analysed using a validated LCMS (liquid chromatography mass spectrometry) method. 

Pharmacokinetics 

A maximum of 5 samples per woman will be collected:

• prior to administration of the first dose of the ACTION III study medication,
• 3 hours after,
• 12 hours after and,
• 1 day after birth.

Cord blood at birth will be used to study the levels in foetal circulation. Using all collected samples, steroid levels will be measured using a validated liquid chromatography-mass spectrometry assay. 

Pharmacodynamic biomarker measurement

Three parameters will be measured as PD markers at an FDA approved facility in India. These include:

• serum cortisol
• glucose and
• white cell counts

Sample size 

A total of 150 women from India and 150 women from Nigerian sites (this includes 50 women from each of the three arms adding to 150 women from each country). 

Implications 

Information on the PK and PD of ACS will generate new knowledge that can inform further ACS dose optimization. This study will contribute towards making ACS safer for mothers and newborns globally.