The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries

The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries Temitope Adesiji Adegboyega, Ebunoluwa Aderonke Adejuyigbe, Olubukola Adeponle Adesina, and 61 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3324018/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Apr, 2024 Read the published version in Trials → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Preterm birth complications are the leading cause of newborn and under-5 mortality. Over 85% of all preterm births occur in the late preterm period i.e., between 34 and <37 weeks of gestation. Antenatal corticosteroids (ACS) prevent mortality and respiratory morbidity when administered to women at high risk of an early preterm birth i.e. < 34 weeks’ gestation. However, the benefits and risks of ACS in the late preterm period are less clear; both guidelines and practices vary between settings. Emerging evidence suggests that the benefits of ACS may be achievable at lower doses than presently used. This trial aims to determine the efficacy and safety of two ACS regimens compared to placebo, when given to women with a high probability of late preterm birth, in hospitals in low-middle income countries (LMICs). Methods: WHO ACTION III trial is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens: dexamethasone phosphate 4x6 mg q12h or betamethasone phosphate 4x2 mg q 12h. The trial is being conducted across seven sites in five countries- Bangladesh, India, Kenya, Nigeria and Pakistan. Eligible women are those with a gestational age between 34 weeks 0 days and 36 weeks 5 days, who have a high probability of preterm birth in next 12 hours to 7 days (up to 36 weeks 6 days gestation). The primary outcome is a composite of stillbirth or neonatal death within 72 hours of birth, or use of newborn respiratory support within 72 hours of birth or prior to discharge from hospital, whichever is earlier. Secondary outcomes include safety and health utilization measures for both women and newborns The sample size is 13,500 women. Discussion: This trial will evaluate the benefits and possible harms of ACS when used in women likely to have a late preterm birth. It will also evaluate a lower-dose ACS regimen based on literature from pharmacokinetic studies. The results of this trial will provide robust critical evidence on the safe and appropriate use of ACS in the late preterm period internationally. Trial registration: ISRCTN11434567. Registered on 7 June 2021; https://doi.org/10.1186/ISRCTN11434567 . antenatal corticosteroids late preterm birth dexamethasone betamethasone low- and middle-income countries Figures Figure 1 Figure 2 Background The global burden of preterm birth Globally, in 2020, an estimated 13.4 million babies were born preterm, with 85% of these births occurring in the late preterm period i.e., between 34 and < 37 weeks’ gestation [ 1 ]. Approximately 65% of all preterm births occurred in South Asian and sub-Saharan African countries [ 1 ]. Complications of preterm birth led to the death of nearly 1 million newborns in the same year and are presently the leading cause of death among children under 5 years of age [ 1 , 2 ]. Preterm newborns are at an increased risk of acute- and long-term respiratory, infectious, and neurological complications. Although these risks are substantially higher in infants born at earlier gestations, late preterm infants also experience a significantly higher rate of morbidity, mortality and adverse neurodevelopment compared to term-born infants [ 3 , 4 ]. Antenatal corticosteroids in the late preterm period Antenatal corticosteroids (ACS) are a key intervention to mitigate the risk of mortality and morbidity resulting from the complications of preterm birth. Evidence from multiple randomized trials largely in high income settings, has shown that when ACS are administered to women with a high probability of preterm birth prior to 34 weeks’ gestation, they can reduce neonatal mortality and respiratory morbidity [ 5 ]. More recently, the World Health Organization (WHO) ACTION I trial has conclusively demonstrated similar results even in low-resource settings, when ACS are used in hospitals in accordance with criteria set out in the guidelines for ACS use by the WHO [ 6 ]. However, the benefits and risks of ACS in the late preterm period are less clear. The most recent update of the Cochrane systematic review on ACS efficacy identified seven trials evaluating ACS in the late preterm period [ 7 ]. The review found no discernable effect of ACS on perinatal or neonatal mortality among studies that enrolled women from 34 weeks 0 days to < 37 weeks gestation, although there was a reduction in the risk of respiratory distress syndrome (RDS) (RR 0.75, 95% CI 0.60, 0.95). A separate systematic review of five ACS trials that enrolled 3844 women from 34 weeks 0 days gestation drew similar conclusions (reduced need for respiratory support, RR = 0.68, 95% CI 0.47–0.98) [ 8 ]. While the Cochrane meta-analysis ACS in the late preterm period included trials from high-, middle-, and low-income countries, a single trial from the United States– the Antenatal Late Preterm Steroid (ALPS Trial) [ 9 ] – accounted for more than 75% of the sample size. The ALPS trial reported that compared to placebo, ACS reduced the need for respiratory support among neonates (RR 0.80, 95% CI 0.66–0.97) although there was no difference in RDS. It has been suggested that the difference may have been driven by reduction in transient tachypnoea of the newborn (TTN) [ 9 ]. The trial also reported an increase in the risk of hypoglycaemia among babies in the ACS arm (RR 1.60, 95% CI 1.37–1.87). Smaller subsequent studies in India and Lebanon (a trial with 310 and a prospective cohort with 295 participants respectively) on ACS in the late preterm period have not reported any reductions in rates of RDS, TTN, or neonatal intensive care unit admissions [ 10 , 11 ]. The WHO ACTION-II trial that randomized 782 women in India between 34 weeks 0 days and 36 weeks 0 days to ACS or placebo did not find differences in benefit or safety outcomes, though this trial was under-powered to reach a clear conclusion [ 12 ]. Concerns regarding ACS safety and efficacy in low- and middle-income countries, including during the late preterm period, were raised by the adverse findings of the Antenatal Corticosteroids Trial (ACT) [ 13 ]. ACT was a community-based, cluster-randomized implementation trial conducted in six LMICs (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia), which evaluated a complex intervention that aimed to scale-up ACS use. The ACT trial reported significantly higher rates of neonatal death, stillbirth and possible maternal infection amongst the intervention group. These harmful effects appeared concentrated in newborns at and above the 25th birthweight percentile, in whom the relative increase in mortality was 30%. As birthweight was used as a proxy measure for gestational age in this trial, it would suggest that larger, more mature newborns (higher gestational age) were potentially at greater risk of mortality [ 13 ]. Evaluating a lower dose of ACS A guiding principle of therapeutics is to give the lowest effective dose required to confer benefit, which can help minimize any risks of harm. Despite being used clinically for over 50 years, the optimal ACS dosing regimen is largely unexplored [ 14 ]. Dose-ranging studies have not been performed for ACS. Clinically recommended ACS regimens today are largely similar to those used in the original Liggins trial of 1972 [ 15 ]. This is a particularly important issue for ACS, which has effects on multiple organ systems in the preterm fetus [ 16 ]. The clinical use of ACS for fetal lung development remains off-label, though injectable steroid preparations are readily available, inexpensive, and have been widely used for decades. Recent animal studies have demonstrated that significantly lower ACS doses than presently used can induce fetal lung maturational changes, suggesting that current ACS regimens in clinical use may expose the fetus to unnecessarily high steroid levels [ 17 , 18 ], which could mediate some of the adverse effects noted in trials. Recent studies of steroids in non-pregnant [ 19 , 20 ] and pregnant women [ 21 ] have provided more information on the pharmacokinetics of ACS. Taken together, these animal and human studies suggest that a fetal steroid concentration of 1–4 ng/ml could bring about a lung maturational response. Pharmacokinetic modelling of conventionally used ACS regimens suggest that fetal steroid levels are approximately 3–4 times higher [ 22 ]. The duration of fetal exposure to ACS at adequate levels is also critical to the maturational response. The ACTION-1 trial reported that longer intervals were associated with better newborn outcomes for early preterm newborns, regardless of gestational age at the time of administration [ 6 ]. There are also concerns regarding the longer-term effects of in-utero exposure to ACS on neurodevelopment, learning, and behavioural outcomes in children [ 24 , 25 ]. These concerns and the possibility that lower ACS doses may still confer benefit, has resulted in clinical trials being initiated with ACS regimens using lower doses than that currently recommended by WHO [ 26 ]. The recent BETADOSE trial in France compared a single injection of betamethasone (half the conventional dose or 11.4 mg) to two injections of betamethasone (full conventional dose or 22.8 mg) for women at risk of preterm birth before 32 weeks of gestation [ 27 ]. The trial results indicated that the half-dose was inferior to the full dose on the need for exogenous surfactant in the newborn on intention-to-treat (RD 2.4%, 95% CI -0.3 to 5.2) as well as on per-protocol analysis (RD 2.2%, 95% CI -0.6 to 5.1). However, it is possible that exposure to prolonged adequate concentrations necessary for fetal lung maturation may not have occurred with the half dose, given the pharmacokinetics of the betamethasone formulation used (Celestone i.e. betamethasone phosphate and acetate). The ACTION III trial will study the efficacy of a lower dose of ACS (betamethasone phosphate 2mg q 12h), which has been selected based on pharmacokinetic modeling toprovide the desired sustained fetal exposure (1–4 ng/ml). International differences in clinical recommendations on the use of ACS in the late preterm period Existing guidelines consistently recommend ACS for women up to 34 weeks gestation [ 28 – 31 ]. There is, however, variation between recommendations on ACS in the late preterm period. The American College of Obstetricians and Gynecologists (USA) guidelines recommend that betamethasone can be considered up to 36 weeks 6 days [ 28 ], while, the 2019 iteration of the European consensus guideline removed the recommendation on the use of ACS in the late preterm period,[ 31 ]. The International Federation of Gynaecology and Obstetrics also recommends against routine use of ACS after 34 weeks of gestation [ 29 ] (Additional file 1). There is currently a lack of clarity on the clinical benefits of ACS use in the late preterm period, and uncertainty about the potential for harm. The WHO ACTION III trial will provide valuable information to fill this gap, generating critical data for updating clinical guidelines internationally on ACS use in the late preterm period. Methods The trial protocol is reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 2) [ 32 ]. Aims and objectives The aim of this trial is to assess the benefits and possible harms of two regimens of ACS;(i) dexamethasone phosphate 4x6 mg q12 h or (ii) betamethasone phosphate 4x2 mg q 12 h) compared to placebo, when given to women in the late preterm period (gestational age of 34 weeks 0 days to 36 weeks 5 days) with a high probability of preterm birth. The primary objectives are to compare the effect of each active ACS arm with placebo on a composite outcome of stillbirth, neonatal death, or use of respiratory support within 72 hours of life or prior to discharge from hospital, whichever is earlier. The secondary objectives are to compare the effects of each ACS regimen versus placebo on maternal and neonatal safety and healthcare utilization outcomes. Trial design ACTION III is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens, dexamethasone phosphate 4x6 mg q12 h regimen and betamethasone phosphate 4x2 mg q 12 h regimen, given to women with a high probability of preterm birth in the late preterm period to improve neonatal outcomes (Fig. 1 ). Study setting This is a multi-country, multi-centre trial that will be conducted in Bangladesh, India, Kenya, Nigeria, and Pakistan, in hospitals where the WHO ACS treatment criteria can reasonably be met [ 30 ]. Specifically, these include hospitals where gestational age assessment can be accurately undertaken, there high likelihood of preterm birth within 7 days of starting ACS therapy, capacity to recognize and rule out any clinical maternal infection, adequate childbirth care is available (including capacity to recognize and safely manage preterm labour and birth) and the preterm newborn can receive adequate care (including resuscitation, kangaroo mother care, thermal care, feeding support, infection treatment and respiratory support including safe use of oxygen and continuous positive airway pressure [CPAP] as needed) [ 30 ]. A total of 29 hospitals are currently recruiting into the trial. The hospitals are largely similar to those that participated in the WHO ACTION I trial [ 6 ]. Although these are hospitals with the capacity to manage women having preterm birth and provide care for preterm newborns with minimal out-referral, they do however experience human resource, and health system challenges that are common in LMICs. Trial activities will be facility-based, with hospital or community follow-up of recruited women and newborns after hospital discharge, to 28 completed days of life. Participants Women with singleton or multiple pregnancy at 34 weeks 0 days to 36 weeks 5 days, with at least one live fetus, and a high probability of late preterm birth will be included. High probability of late preterm birth (up to 36 weeks 6 days) is defined as birth expected between 12 hours and 7 days after randomization as a result of one of the following: preterm labour with intact membranes, where preterm labour is defined as at least 6 regular contractions/hour and at least one of the following: cervix ≥ 3 cm dilated or 75% effaced; or membranes rupture without preterm labour (preterm labor defined as above; or planned delivery by induction of labour or caesarean section between 24 hours and 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36 weeks 5 days at the latest, whereas a caesarean section must be scheduled by 36 weeks 6 days at the latest. In order to assess eligibility, a good-quality antenatal ultrasound with reliable gestational age estimation must be available. If a woman has not received an obstetric ultrasound of reasonable quality for gestational age estimation previously (at least two weeks prior to screening) during the current pregnancy, it must be performed as part of eligibility assessment during the screening process. A woman is ineligible if she is expected to give birth in < 12 hours (i.e., if she had ruptured membranes with cervix dilated ≥ 3 cm or effaced ≥ 75%, or with more than 6 contractions per hour or both cervical changes and contractions as specified; or cervical dilation ≥ 8 cm with intact membranes) or; if there is evidence of non-reassuring fetal status or other clinical indication requiring immediate preterm delivery. She will be excluded if the obstetric care provider has a clinical suspicion or evidence of clinical chorioamnionitis or severe infection; if she has received any systemic corticosteroid in the last two weeks (outside of trial); or if no prior ultrasound assessment of gestational age is available and an immediate ultrasound examination is not possible. Other reasons a woman may be ineligible to participate include a major or lethal congenital fetal anomaly being identified, confirmed COVID infection deemed severe enough to require steroid treatment as per national standards of COVID treatment, is unwilling or unable to provide consent or assent (including due to active labour), or is currently participating in another clinical trial, or has previously participated in any ACTION trial or any other clinical indication where the treating clinician considers corticosteroids to be contraindicated. Intervention and control The intervention regimens are (a) dexamethasone phosphate 4x6 mg q12 h, or (b) betamethasone phosphate 4x2 mg q12 h. A single course of 6 mg intramuscular (IM) dexamethasone phosphate or 2 mg IM betamethasone phosphate is administered every 12 hours, to a total of four doses or until birth occurs, whichever occurs first. The control arm will receive four saline injections of the same volume at the same dosing intervals. Outcomes Primary outcomes. Stillbirth or neonatal death within 72 hours of birth or use of respiratory support within 72 hours of birth or prior to discharge from the hospital, whichever is earlier. Use of respiratory support is defined as any one of the following: (i) use of invasive mechanical ventilation, (ii) continuous use of CPAP for 12 hours or more with an FiO2 ≥ 0.4 at any time, or (iii) continuous use of supplementary oxygen for 24 hours or more with an FiO2 ≥ 0.4 at any time. Secondary outcomes (also see additional file 3). Newborn mortality and respiratory morbidity outcomes: stillbirth; neonatal death within 72 hours, 7 days, and 28 days of birth; resuscitation at birth (i.e., use of positive pressure ventilation for > 1 min at birth); severe respiratory distress within 72 hours of birth or prior to discharge from the hospital; use of respiratory support within 72 hours of birth or prior to discharge from the hospital (as defined above); death or mechanical ventilation or very high CPAP settings (≥ 8 cm water pressure and ≥ 0.7 FiO 2 ) in the first 72 hours of birth; and cause-specific mortality. Newborn safety outcomes: neonatal sepsis in the first 7 days of birth; hypoglycaemia in the first 36 hours after birth. Newborn health service utilization outcomes: admission to neonatal care unit in the first three days after birth; duration of birth hospitalization; and any parenteral antibiotic use in the first seven days after birth. Maternal safety outcomes: maternal death; possible maternal bacterial infection during hospital admission(s); chorioamnionitis; and postpartum endometritis. Maternal health service utilization outcomes: duration of hospital stay; any therapeutic antibiotic use; and any antibiotic use. Participant timeline The participant timeline and follow-up process are summarized in Fig. 2 . Screening, informed consent, and randomization will take place in study hospitals where the mother has presented and will give birth. Randomized women and their newborns will be followed up during the hospital stay and then to 28 days after birth. After randomization, study data will be recorded by trained research staff in participating hospitals. At the time of discharge, the woman will be advised to return to the study hospital or call the site investigators in the event of any adverse outcomes for her or her baby. All randomized participants (women and newborns) will have scheduled postpartum/postnatal follow-up visits conducted on day 7 and day 28. Screening, informed consent, and recruitment to the trial Pregnant women admitted to the antenatal, labour ward or emergency admission area in the third trimester at participating hospitals will be routinely evaluated on arrival by obstetric care physicians. Women with clinical features or indications suggestive of preterm birth in the late preterm period will be informed of the study. Study staff (including research or clinical staff trained in study procedures) will conduct formal screening using a standardized screening form. The screening population is women who are between 34 weeks 0 days and 36 weeks 5 days and who are expected to deliver between 12 hours and 7 days. Screening will consist of three key activities to assess women for eligibility and trial entry: assessment of gestational age (34 weeks 0 days to 36 weeks 5 days), assessment if the delivery is likely between 12 hours and 7 days, and assessment for the presence of any exclusion criteria. Gestational age will be based on a best obstetric estimate combining information from the last menstrual period, regularity of cycles, and informed by the earliest ultrasound obtained in the pregnancy. Women will receive an ultrasound assessment for gestational age as part of this screening process if an obstetric ultrasound of reasonable quality for gestational age estimation has not been performed during the current pregnancy at least 2 weeks prior to the screening. In these screening ultrasounds, biometric measurement and gestational age assignment will be performed using INTERGROWTH-21st project biometry guidelines and fetal growth curves, respectively [ 33 ] (Additional file 3. Figure 1 ). Prior to enrolling patients, all study sites received standardized training in the ultrasound evaluation of fetal biometry in the third trimester. Throughout the study, images will be reviewed regularly for quality assurance. If women are unable to complete the full screening and informed consent process (due to distress, or other reasons), they will not be recruited. All women will receive information about the trial in their language of choice via an information sheet. If willing to participate, the informed consent form will be signed by the participant and study staff. Allocation sequence generation Participants will be randomly assigned to either dexamethasone-4x6 mg or betamethasobe-4x2 mg ACS regimen, or placebo in a 1:1:1 allocation as per a computer-generated randomization sequence, in balanced permuted blocks. The randomization sequence will be generated by a researcher external to the ACTION III trial. The assignment schedule will be stored at WHO headquarters in Geneva, Switzerland. All sites will receive treatment packs according to the randomization sequence, assembled in special dispensers. Facility study team members at participating sites will remove and open the next pack from the dispenser for allocation as per a set standard operating procedure. Allocation concealment and blinding Allocation concealment will be achieved by having identical treatment packs across the three arms. At the time of randomization, study staff will take the next sequentially numbered pack from the box (Additional file 3, Fig. 2 ). The IM injections will be administered by the hospital staff nurses according to study procedures. Participants, care providers, investigators, the WHO trial coordinating unit, and data collectors will be blinded to the group allocation. Each active drug will have its own saline placebo identically packaged to allow for blinding of the three arms. Betamethasone phosphate (4mg/ml as 1ml ampules) and its placebo (1ml normal saline) will be manufactured by Recipharm AB. Dexamethasone (4mg/ml as 1ml ampules) and its placebo (1ml normal saline) will be manufactured by Fresenius Kabi. All three arms will have identical packaging, appearance, labelling, and volumes to be administered. Emergency unblinding procedures The principal investigators at each site and a designated WHO project manager will receive the participants’ treatment codes in the form of separate sealed envelopes that contain the treatment allocation for each participant, in case the code for a participant’s treatment needs to be broken urgently. Retention and follow-up procedures The study team will request contact details (address, phone number, relatives) from randomized women, in order to facilitate communication at follow-up to 28 days after birth by home visit. Data collectors will make every reasonable effort to follow the woman and her newborn for the entire study period. After randomization, outcomes occurring in the facility (prior to discharge) will be captured by research study staff working in participating hospitals. At the time of discharge, the woman will be advised to return to the study hospital or call the site investigators in the event of any adverse outcomes for her or her baby. Data management Data will be managed centrally by a data management team, supervised directly by WHO project managers. The study statistician will be responsible for the development of the statistical analysis plan and reporting to the DSMB. A web-based, Good Clinical Practice (GCP) compliant data management platform (Kamolo, Centro Rosarino Estudios Perinatales (CREP) will be used, and be overseen by the site data managers. All data will be collected in study centres on paper case report forms (CRFs). Quality control will be performed at each site, and a validation system will be built into the data entry and management system to ensure consistency, accuracy and completeness of the data collected. Confidentiality To ensure participant confidentiality, each participant will be identified by a unique ID number. The local trial register linking personal information and trial ID numbers, and all personal information of participants, will be kept separate from the CRFs. Trial documents will be kept securely under lock and key in the research offices and will not be accessible, other than to the researchers. Data will be entered by trial ID number in the password-protected data management system to which only trial staff will have access. The trial report will not contain the names of any participants, and after completion of the trial, the trial documents will be archived in accordance with institutional and national rules for clinical research archiving. Statistical methods Sample size It is estimated that the prevalence of the primary composite outcome in the control arm will be between 10–12% based on data from ACTION I [ 6 ], ACTION II [ 12 ], and the ALPS study [ 9 ] on late preterm births. A reduction of 20% is the minimal change deemed acceptable in the composite outcome, in order to change practice. Assuming a 2.5% loss to follow-up, a sample size of 4,500 women per arm in the three-arm trial will have at least 80% power and α at 0.027 to account for multiple comparisons using Dunnett's method to detect a 20% reduction in the composite primary outcome. Statistical methods for primary and secondary outcomes The primary intention-to-treat analysis will be based on all participants (i.e. newborns of randomized women, and women) with outcome data available. Data from participants who withdraw their consent for their data to be used will be excluded from the analysis and considered lost to follow-up. Comparative analyses between trial arms will consider multiplicity as both ACS arms use the same placebo arm as a comparator: confidence intervals for the intervention effect (e.g. risk ratios) will be computed to have a joint 95% coverage probability using Dunnett’s method [ 34 ]. The primary outcome and most secondary outcomes are binary variables. For these outcomes, the total number of observations, number of missing values and percentages will be reported per arm. Comparisons of outcomes between each intervention arm and the placebo arm, will be described using risk ratios. Risk ratios will be estimated by binomial generalised estimating equations with log links and robust standard errors to account for potential correlation of outcomes among babies born to the same mother. The primary analysis will include arm and site as fixed covariates, and a secondary analysis will also adjust for any baseline covariates for which there is an important imbalance at baseline. If the log binomial models fail to converge, then Poisson models with robust standard errors will be used. For continuous outcomes (duration of birth hospitalization for the mothers and the babies), the number of participants, missing values, minimum, maximum, means, and standard deviations by arm will be reported. Comparisons of each ACS dose arm against the placebo arm will be described as mean differences. Duration of birth hospitalization (continuous neonatal outcome) for all babies will be compared between arms as mean differences estimated using mixed linear models, including a maternal random effect to account for potential correlation of outcomes among babies born to the same mother. The median duration and Kaplan Meier curves will also be reported by arm. Interim analyses A first interim analysis by the Data Safety Monitoring Board (DSMB) is tentatively planned at 60% recruitment completion, however reporting on safety criteria (including serious adverse events) will occur quarterly. At this first interim analysis, the DSMB will look at the performance of both active arms combined, versus placebo. This is to minimize unnecessary exposure of additional women to the placebo (in case the combined arms are better than placebo). If the analysis reveals that the combined ACS arms are superior to placebo with p < 0.001 (Peto’s rule), then the DSMB could recommend cessation of the placebo arm (after confirming that there is statistical evidence that at least one ACS arm is better than placebo with p < 0.025, and for safety p < 0.01 for mortality. However, recommendations after the results of an interim analysis will not be guided only by statistical considerations, but also by practical issues (adverse events, unanticipated costs), as well as clinical considerations or external new information. In the event of both ACS regimens being superior to placebo, and based on a benefit-risk assessment, the DSMB could recommend a non-inferiority comparison between the two active arms.. Subgroup analyses Pre- and post-randomization subgroup analyses will be conducted for the primary endpoint. Pre-randomization subgroups include different indications for enrolment (i.e. rupture of membranes, preterm labour with intact membranes, planned termination), gestational age at enrolment ( 36 weeks 0 days), study site, and single vs multiple births. Post-randomization subgroups include gestational age at birth (preterm ( 12 to 24 hours, > 24 hours to 7 days, > 7 days), use of tocolytics post-randomization, appropriate size for gestational age vs small for gestational age, and mode of birth (vaginal vs caesarean section). Statistical tests for effect modification by the different factors mentioned above will be performed. While post-randomization subgroup analyses are at risk of bias, in the current trial we believe there are good scientific reasons to investigate these subgroups as there are plausible reasons why the treatment effects could be different. Also, these subgroups are clinically important, and are explicitly considered in the latest update of WHO’s ACS recommendations [ 26 ]. Before conducting these post-randomization subgroup analyses, we will first examine whether the intervention has an effect on the stratifying variable. Trial oversight Monitoring procedures have been prepared in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonised tripartite guideline for Good Clinical Practice E6 (R2). Monitoring activities will be conducted overall, per site and per hospital. Standard operating procedures will be prepared for all monitoring activities and will govern all monitoring procedures. Monitoring will be intensive throughout the trial recruitment period and will be conducted by independent trial monitors, principal investigators and co-investigators, and WHO trial coordinating unit (TCU) comprising WHO staff from two WHO Departments (Maternal, Newborn, Child, and Adolescent Health and Ageing, and Sexual and Reproductive Health and Research). Day-to-day oversight will be done by the trial steering committee comprising TCU and the principal investigators at each site. A technical Trial Advisory Group (external independent scientists with expertise in the area of preterm birth) led by an independent chair will advise the trial steering committee. A study DSMB will comprise five members, including an independent chair, a statistician, and three technical experts familiar with the intervention, maternal and newborn health care, and clinical trial methodology. The DSMB will monitor adverse events on an ongoing basis to look for emerging safety risks and advise the trial coordinating unit (TCU) accordingly. Ethical considerations The trial protocol was reviewed and approved by the WHO Ethics Review Committee. All participating sites received approval from the relevant institutional scientific and ethical review committees in the respective country (as well as required permissions from the relevant national regulatory authorities) (Additional file 6). Any modifications to the protocol which may impact the conduct of the study, a potential benefit of the study participants, or may affect their safety, including changes in study objectives, study design, study population, sample sizes, study procedures, or other significant aspects will require a formal amendment to the protocol. Such amendments will be agreed upon by study co-investigators and submitted to WHO ethical review committee and participating institutional ethical review committees prior to implementation. Discussion As the leading cause of neonatal and child mortality and morbidity, preterm birth is a critical global public health priority. Although > 80% of all preterm births occur in the late preterm period, there is still uncertainty on the balance of benefits and risks of using ACS in women at risk of a late preterm birth. This is evident from the divergent recommendations from different international guidelines.[ 28 , 29 ] In WHO’s latest ACS recommendations, the Guideline Development Group noted that the ACTION III Trial would provide the necessary evidence to inform future recommendations [ 26 ]. The optimal dose of ACS that can confer benefit while minimizing unnecessary fetal exposure has not been studied extensively. This is particularly important, as ACS are a potent developmental modulator, and in-utero exposure (particularly for infants born in the late preterm or term period) has been linked with worse neurodevelopmental outcomes in childhood [ 24 , 25 ]. There have been recent calls for trials on lower doses of steroids [ 35 ]. The BETADOSE trial in France was the first trial of a single half-dose versus full-dose betamethasone [ 27 ]. The betamethasone 4 x 2mg regimen planned in the ACTION III trial takes into consideration the pharmacokinetics of ACS and the need for a prolonged exposure to an adequate concentration over a longer period. The ACTION III trial will also clarify some of the uncertainties raised by the Antenatal Corticosteroids implementation trial (ACT) [ 13 ] that was conducted in LMICs. The results of the ACTION III trial will contribute valuable information to bridge the evidence gap on the balance of benefits and risks of ACS in the late preterm period. Given the divergence in guidelines on ACS use in the late preterm period issued by various international and national bodies, in high- and low-income settings, the evidence from this trial will facilitate recommendations on the use of ACS in the late preterm period globally. Abbreviations ACS Antenatal corticosteroids ACT Antenatal Corticosteroids Trial ACTION Antenatal Corticosteroids for Improving Outcomes in preterm Newborns DSMB Data and Safety Monitoring Board GCP Good clinical practice SPIRIT Standard Protocol Items:Recommendations for Interventional Trials TCU Trial Coordinating Unit WHO World Health Organization Declarations Trial status This manuscript is based on the current version of the protocol, version 1.16, which was approved by the WHO Ethics Review Committee on 11 th Apr 2023. Recruitment started on 15 July 2022 and is expected to be complete by December 2026. Ethics approval and consent to participate: Approved 03/03/2021, WHO Ethics Review Committee (20, Avenue Appia, Ch-1211, Geneva 27, Switzerland; +41 (0)22 791 1479; [email protected] ), ref: 0003488). Consent for publication . The members of the WHO ACTION Trials Collaboration consent to publication. Availability of data and materials . Not available. Competing interests. The authors declare that they have no competing interests. Funding. This trial is supported by the Bill and Melinda Gates Foundation (INV-005390). The funder had no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Authors’ contributions: ADC, RB, OTO coordinated the writing of the study protocol, with input from the Technical Coordinating Unit (SG, TL, NM, MN, SR, JV), Principal Investigators and the Technical Advisory Group. All named members of the Collaboration had an opportunity to review and discuss the study protocol. WHO is the sponsor for the ACTION-III Trial, and takes overall responsibility for collection, management, analysis, and interpretation of data, writing of the report, and the decision to submit the report for publication. WHO can be contacted at [email protected] . The authors read and approved the final manuscript. Acknowledgements. WHO gratefully acknowledges the contribution of the following experts: Technical Advisory Group: Elizabeth Molyneaux, Khalid Yunis, Hadiza Galadanci, Jeeva Sankar, Andrew Shennan Data Safety and Monitoring Board: Betty Kirkwood, Jon Deeks, Justus Hofmeyr, Siddarth Ramji and Elizabeth Bukusi The WHO ACTION Trial Collaborators (listed alphabetically by family name): Temitope Adesiji Adegboyega, Ebunoluwa Aderonke Adejuyigbe, Olubukola Adeponle Adesina, Babalola Adeyemi, Salahuddin Ahmed, Francis Akinkunmi, Jalemba Aluvaala, Henry Anyabolu, Shabina Ariff, Sugandha Arya, Ibrahim Awowole, Adejumoke Idowu Ayede, Neelofur Babar, Sumitra Bachani, Rajiv Bahl, Abdullah H. Baqui, Harish Chellani, Saleha Begum Chowdhury, Lynn M Coppola, Simon Cousens, Pradeep K Debata, Ayesha DeCosta*, Sangappa M Dhaded, Kasturi V Donimath, Adegoke Gbadegesin Falade, Shivaprasad S Goudar, Shuchita Gupta, George N. Gwako, Theresa Azonima Irinyenikan, Dennis Anthony Isah, Nigar Jabeen, Arshia Javed, Naima T Joseph, Rasheda Khanam, John Kinuthia, Oluwafemi Kuti, Tina Lavin, Ahmed R Laving, Sandhya Maranna, Nicole Minckas, Pratima Mittal, Diwakar Mohan, Sidrah Nausheen, My Huong Nguyen, Olufemi T Oladapo*, Olanike Abosede Olutekunbi, Rosena Olubanke Oluwafemi, Alfred Osoti, Yeshita V Pujar, Zahida P. Qureshi, Suman PN Rao, Sophie Sarrassat, M. A. Shahed, Mohammod Shahidullah, Lumaan Sheikh, Manjunath S Somannavar, Sajid Soofi, Jyotsna Suri, Sunil S Vernekar, Joshua P Vogel, Nitya Wadhwa, Prakash K Wari, Fred Were, Blair J Wylie References Ohuma E, Moller A-B, Bradley E. (in press). National, regional, and worldwide estimates of preterm birth in 2020,with trends from 2010: a systematic analysis. Lancet 2023. Levels & trends in child mortality. Report 2022. New York: United Nations Inter-Agency Group for Child Mortality Estimation (UNIGME); 2023. Natarajan G, Shankaran S. 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Pharmacokinetics and pharmacodynamics of intramuscular and oral betamethasone and dexamethasone in reproductive age women in India. Clin Transl Sci. 2020;13(2):391–9. http://dx.doi.org/10.1111/cts.12724 . Krzyzanski W, Milad MA, Jobe AH, Peppard T, Bies RR, Jusko WJ. Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women. J Pharmacokinet Pharmacodyn. 2021;48(3):411–38. http://dx.doi.org/10.1007/s10928-021-09755-y . Foissac F, Zheng Y, Hirt D, Lui G, Bouazza N, Ville Y, et al. Maternal betamethasone for prevention of respiratory distress syndrome in neonates: Population pharmacokinetic and pharmacodynamic approach. Clin Pharmacol Ther. 2020;108(5):1026–35. http://dx.doi.org/10.1002/cpt.1887 . Krzyzanski W, Milad MA, Jobe AH, Jusko WJ. Minimal physiologically-based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids. 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Available from: https://www.who.int/publications/i/item/9789240057296 . Schmitz T, Doret-Dion M, Sentilhes L, Parant O, Claris O, Renesme L, et al. Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2022;400(10352):592–604. http://dx.doi.org/10.1016/S0140-6736(22)01535-5 . Committee opinion no. 713: Antenatal corticosteroid therapy for fetal maturation: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017;130(2):e102–9. http://dx.doi.org/10.1097/aog.0000000000002237 . Norman J, Shennan A, Jacobsson B, Stock SJ, FIGO Working Group for Preterm Birth. FIGO good practice recommendations on the use of prenatal corticosteroids to improve outcomes and minimize harm in babies born preterm. Int J Gynaecol Obstet. 2021;155(1):26–30. http://dx.doi.org/10.1002/ijgo.13836 . Medley N, Poljak B, Mammarella S, Alfirevic Z. Clinical guidelines for prevention and management of preterm birth: a systematic review. BJOG 2018;125(11):1361–9. http://dx.doi.org/10.1111/1471-0528.15173 . Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European consensus guidelines on the management of respiratory distress syndrome – 2019 update. Neonatology. 2019;115(4):432–50. http://dx.doi.org/10.1159/000499361 . Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. http://dx.doi.org/10.1136/bmj.e7586 . (jan08 15. Papageorghiou AT, Kemp B, Stones W, Ohuma EO, Kennedy SH, Purwar M, et al. Ultrasound-based gestational-age estimation in late pregnancy: International late pregnancy dating. Ultrasound Obstet Gynecol. 2016;48(6):719–26. http://dx.doi.org/10.1002/uog.15894 . Dunnett CW. New tables for multiple comparisons with a control. Biometrics. 1964;20(3):482. http://dx.doi.org/10.2307/2528490 . Ninan K, Morfaw F, Murphy KE, Beyene J, McDonald SD. Neonatal and maternal outcomes of lower versus standard doses of antenatal corticosteroids for women at risk of preterm delivery: A systematic review of randomized controlled trials. J Obstet Gynaecol Can 2021;43(1):74–81. http://dx.doi.org/10.1016/j.jogc.2020.02.127 . Supplementary Additional file 6 is not available with this version. Supplementary Files Additionalfile1.Internationalrecommendations.docx Additional file 1: International recommendations on use of antenatal corticosteroids in the late preterm period Additionalfile2SPIRITchecklist.doc Additional file 2. SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. Additionalfile3.Supplementaryfigures.docx Additional file 3: Supplementary figures Additionalfile4Primaryandsecondaryoutcomes.docx Additional file 4: ACTION-III trial: primary and secondary outcomes. Additionalfile5.ACTIONIIIInformationandConsent.docx Additional file 5: ACTION III trial informed consent form, v1.4, 2 Dec 2022 Additionalfile7.NationalIRBapprovals.docx Additional file 7: List of Institutional Review Boards who have approved the ACTION-III trial Cite Share Download PDF Status: Published Journal Publication published 12 Apr, 2024 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 25 Oct, 2023 Reviewers invited by journal 25 Oct, 2023 Editor assigned by journal 24 Oct, 2023 First submitted to journal 27 Sep, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Approximately 65% of all preterm births occurred in South Asian and sub-Saharan African countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Complications of preterm birth led to the death of nearly 1\u0026nbsp;million newborns in the same year and are presently the leading cause of death among children under 5 years of age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Preterm newborns are at an increased risk of acute- and long-term respiratory, infectious, and neurological complications. Although these risks are substantially higher in infants born at earlier gestations, late preterm infants also experience a significantly higher rate of morbidity, mortality and adverse neurodevelopment compared to term-born infants [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAntenatal corticosteroids in the late preterm period\u003c/h2\u003e \u003cp\u003eAntenatal corticosteroids (ACS) are a key intervention to mitigate the risk of mortality and morbidity resulting from the complications of preterm birth. Evidence from multiple randomized trials largely in high income settings, has shown that when ACS are administered to women with a high probability of preterm birth prior to 34 weeks\u0026rsquo; gestation, they can reduce neonatal mortality and respiratory morbidity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. More recently, the World Health Organization (WHO) ACTION I trial has conclusively demonstrated similar results even in low-resource settings, when ACS are used in hospitals in accordance with criteria set out in the guidelines for ACS use by the WHO [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the benefits and risks of ACS in the late preterm period are less clear.\u003c/p\u003e \u003cp\u003eThe most recent update of the Cochrane systematic review on ACS efficacy identified seven trials evaluating ACS in the late preterm period [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The review found no discernable effect of ACS on perinatal or neonatal mortality among studies that enrolled women from 34 weeks 0 days to \u0026lt;\u0026thinsp;37 weeks gestation, although there was a reduction in the risk of respiratory distress syndrome (RDS) (RR 0.75, 95% CI 0.60, 0.95). A separate systematic review of five ACS trials that enrolled 3844 women from 34 weeks 0 days gestation drew similar conclusions (reduced need for respiratory support, RR\u0026thinsp;=\u0026thinsp;0.68, 95% CI 0.47\u0026ndash;0.98) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the Cochrane meta-analysis ACS in the late preterm period included trials from high-, middle-, and low-income countries, a single trial from the United States\u0026ndash; the Antenatal Late Preterm Steroid (ALPS Trial) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] \u0026ndash; accounted for more than 75% of the sample size. The ALPS trial reported that compared to placebo, ACS reduced the need for respiratory support among neonates (RR 0.80, 95% CI 0.66\u0026ndash;0.97) although there was no difference in RDS. It has been suggested that the difference may have been driven by reduction in transient tachypnoea of the newborn (TTN) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The trial also reported an increase in the risk of hypoglycaemia among babies in the ACS arm (RR 1.60, 95% CI 1.37\u0026ndash;1.87). Smaller subsequent studies in India and Lebanon (a trial with 310 and a prospective cohort with 295 participants respectively) on ACS in the late preterm period have not reported any reductions in rates of RDS, TTN, or neonatal intensive care unit admissions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The WHO ACTION-II trial that randomized 782 women in India between 34 weeks 0 days and 36 weeks 0 days to ACS or placebo did not find differences in benefit or safety outcomes, though this trial was under-powered to reach a clear conclusion [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConcerns regarding ACS safety and efficacy in low- and middle-income countries, including during the late preterm period, were raised by the adverse findings of the Antenatal Corticosteroids Trial (ACT) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. ACT was a community-based, cluster-randomized implementation trial conducted in six LMICs (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia), which evaluated a complex intervention that aimed to scale-up ACS use. The ACT trial reported significantly higher rates of neonatal death, stillbirth and possible maternal infection amongst the intervention group. These harmful effects appeared concentrated in newborns at and above the 25th birthweight percentile, in whom the relative increase in mortality was 30%. As birthweight was used as a proxy measure for gestational age in this trial, it would suggest that larger, more mature newborns (higher gestational age) were potentially at greater risk of mortality [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvaluating a lower dose of ACS\u003c/h2\u003e \u003cp\u003eA guiding principle of therapeutics is to give the lowest effective dose required to confer benefit, which can help minimize any risks of harm. Despite being used clinically for over 50 years, the optimal ACS dosing regimen is largely unexplored [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Dose-ranging studies have not been performed for ACS. Clinically recommended ACS regimens today are largely similar to those used in the original Liggins trial of 1972 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This is a particularly important issue for ACS, which has effects on multiple organ systems in the preterm fetus [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The clinical use of ACS for fetal lung development remains off-label, though injectable steroid preparations are readily available, inexpensive, and have been widely used for decades.\u003c/p\u003e \u003cp\u003eRecent animal studies have demonstrated that significantly lower ACS doses than presently used can induce fetal lung maturational changes, suggesting that current ACS regimens in clinical use may expose the fetus to unnecessarily high steroid levels [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], which could mediate some of the adverse effects noted in trials. Recent studies of steroids in non-pregnant [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and pregnant women [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] have provided more information on the pharmacokinetics of ACS. Taken together, these animal and human studies suggest that a fetal steroid concentration of 1\u0026ndash;4 ng/ml could bring about a lung maturational response. Pharmacokinetic modelling of conventionally used ACS regimens suggest that fetal steroid levels are approximately 3\u0026ndash;4 times higher [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The duration of fetal exposure to ACS at adequate levels is also critical to the maturational response. The ACTION-1 trial reported that longer intervals were associated with better newborn outcomes for early preterm newborns, regardless of gestational age at the time of administration [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are also concerns regarding the longer-term effects of in-utero exposure to ACS on neurodevelopment, learning, and behavioural outcomes in children [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These concerns and the possibility that lower ACS doses may still confer benefit, has resulted in clinical trials being initiated with ACS regimens using lower doses than that currently recommended by WHO [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The recent BETADOSE trial in France compared a single injection of betamethasone (half the conventional dose or 11.4 mg) to two injections of betamethasone (full conventional dose or 22.8 mg) for women at risk of preterm birth before 32 weeks of gestation [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The trial results indicated that the half-dose was inferior to the full dose on the need for exogenous surfactant in the newborn on intention-to-treat (RD 2.4%, 95% CI -0.3 to 5.2) as well as on per-protocol analysis (RD 2.2%, 95% CI -0.6 to 5.1). However, it is possible that exposure to prolonged adequate concentrations necessary for fetal lung maturation may not have occurred with the half dose, given the pharmacokinetics of the betamethasone formulation used (Celestone i.e. betamethasone phosphate and acetate). The ACTION III trial will study the efficacy of a lower dose of ACS (betamethasone phosphate 2mg q 12h), which has been selected based on pharmacokinetic modeling toprovide the desired sustained fetal exposure (1\u0026ndash;4 ng/ml).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInternational differences in clinical recommendations on the use of ACS in the late preterm period\u003c/h2\u003e \u003cp\u003eExisting guidelines consistently recommend ACS for women up to 34 weeks gestation [\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. There is, however, variation between recommendations on ACS in the late preterm period. The American College of Obstetricians and Gynecologists (USA) guidelines recommend that betamethasone can be considered up to 36 weeks 6 days [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], while, the 2019 iteration of the European consensus guideline removed the recommendation on the use of ACS in the late preterm period,[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The International Federation of Gynaecology and Obstetrics also recommends against routine use of ACS after 34 weeks of gestation [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] (Additional file 1).\u003c/p\u003e \u003cp\u003eThere is currently a lack of clarity on the clinical benefits of ACS use in the late preterm period, and uncertainty about the potential for harm. The WHO ACTION III trial will provide valuable information to fill this gap, generating critical data for updating clinical guidelines internationally on ACS use in the late preterm period.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cp\u003eThe trial protocol is reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 2) [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eAims and objectives\u003c/h2\u003e\n\u003cp\u003eThe aim of this trial is to assess the benefits and possible harms of two regimens of ACS;(i) dexamethasone phosphate 4x6 mg q12 h or (ii) betamethasone phosphate 4x2 mg q 12 h) compared to placebo, when given to women in the late preterm period (gestational age of 34 weeks 0 days to 36 weeks 5 days) with a high probability of preterm birth. The primary objectives are to compare the effect of each active ACS arm with placebo on a composite outcome of stillbirth, neonatal death, or use of respiratory support within 72 hours of life or prior to discharge from hospital, whichever is earlier. The secondary objectives are to compare the effects of each ACS regimen versus placebo on maternal and neonatal safety and healthcare utilization outcomes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eTrial design\u003c/h2\u003e\n\u003cp\u003eACTION III is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens, dexamethasone phosphate 4x6 mg q12 h regimen and betamethasone phosphate 4x2 mg q 12 h regimen, given to women with a high probability of preterm birth in the late preterm period to improve neonatal outcomes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eStudy setting\u003c/h3\u003e\n\u003cp\u003eThis is a multi-country, multi-centre trial that will be conducted in Bangladesh, India, Kenya, Nigeria, and Pakistan, in hospitals where the WHO ACS treatment criteria can reasonably be met [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. Specifically, these include hospitals where gestational age assessment can be accurately undertaken, there high likelihood of preterm birth within 7 days of starting ACS therapy, capacity to recognize and rule out any clinical maternal infection, adequate childbirth care is available (including capacity to recognize and safely manage preterm labour and birth) and the preterm newborn can receive adequate care (including resuscitation, kangaroo mother care, thermal care, feeding support, infection treatment and respiratory support including safe use of oxygen and continuous positive airway pressure [CPAP] as needed) [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eA total of 29 hospitals are currently recruiting into the trial. The hospitals are largely similar to those that participated in the WHO ACTION I trial [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although these are hospitals with the capacity to manage women having preterm birth and provide care for preterm newborns with minimal out-referral, they do however experience human resource, and health system challenges that are common in LMICs. Trial activities will be facility-based, with hospital or community follow-up of recruited women and newborns after hospital discharge, to 28 completed days of life.\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants\u003c/h2\u003e\n\u003cp\u003eWomen with singleton or multiple pregnancy at 34 weeks 0 days to 36 weeks 5 days, with at least one live fetus, and a high probability of late preterm birth will be included. High probability of late preterm birth (up to 36 weeks 6 days) is defined as birth expected between 12 hours and 7 days after randomization as a result of one of the following:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003epreterm labour with intact membranes, where preterm labour is defined as at least 6 regular contractions/hour and at least one of the following: cervix\u0026thinsp;\u0026ge;\u0026thinsp;3 cm dilated or 75% effaced; or\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003emembranes rupture without preterm labour (preterm labor defined as above; or\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eplanned delivery by induction of labour or caesarean section between 24 hours and 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36 weeks 5 days at the latest, whereas a caesarean section must be scheduled by 36 weeks 6 days at the latest.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIn order to assess eligibility, a good-quality antenatal ultrasound with reliable gestational age estimation must be available. If a woman has not received an obstetric ultrasound of reasonable quality for gestational age estimation previously (at least two weeks prior to screening) during the current pregnancy, it must be performed as part of eligibility assessment during the screening process.\u003c/p\u003e\n\u003cp\u003eA woman is ineligible if she is expected to give birth in \u0026lt;\u0026thinsp;12 hours (i.e., if she had ruptured membranes with cervix dilated\u0026thinsp;\u0026ge;\u0026thinsp;3 cm or effaced\u0026thinsp;\u0026ge;\u0026thinsp;75%, or with more than 6 contractions per hour or both cervical changes and contractions as specified; or cervical dilation\u0026thinsp;\u0026ge;\u0026thinsp;8 cm with intact membranes) or; if there is evidence of non-reassuring fetal status or other clinical indication requiring immediate preterm delivery. She will be excluded if the obstetric care provider has a clinical suspicion or evidence of clinical chorioamnionitis or severe infection; if she has received any systemic corticosteroid in the last two weeks (outside of trial); or if no prior ultrasound assessment of gestational age is available and an immediate ultrasound examination is not possible. Other reasons a woman may be ineligible to participate include a major or lethal congenital fetal anomaly being identified, confirmed COVID infection deemed severe enough to require steroid treatment as per national standards of COVID treatment, is unwilling or unable to provide consent or assent (including due to active labour), or is currently participating in another clinical trial, or has previously participated in any ACTION trial or any other clinical indication where the treating clinician considers corticosteroids to be contraindicated.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eIntervention and control\u003c/h2\u003e\n\u003cp\u003eThe intervention regimens are (a) dexamethasone phosphate 4x6 mg q12 h, or (b) betamethasone phosphate 4x2 mg q12 h. A single course of 6 mg intramuscular (IM) dexamethasone phosphate or 2 mg IM betamethasone phosphate is administered every 12 hours, to a total of four doses or until birth occurs, whichever occurs first. The control arm will receive four saline injections of the same volume at the same dosing intervals.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcomes.\u003c/strong\u003e Stillbirth or neonatal death within 72 hours of birth or use of respiratory support within 72 hours of birth or prior to discharge from the hospital, whichever is earlier. Use of respiratory support is defined as any one of the following: (i) use of invasive mechanical ventilation, (ii) continuous use of CPAP for 12 hours or more with an FiO2\u0026thinsp;\u0026ge;\u0026thinsp;0.4 at any time, or (iii) continuous use of supplementary oxygen for 24 hours or more with an FiO2\u0026thinsp;\u0026ge;\u0026thinsp;0.4 at any time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes (also see additional file 3).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNewborn mortality and respiratory morbidity outcomes: stillbirth; neonatal death within 72 hours, 7 days, and 28 days of birth; resuscitation at birth (i.e., use of positive pressure ventilation for \u0026gt;\u0026thinsp;1 min at birth); severe respiratory distress within 72 hours of birth or prior to discharge from the hospital; use of respiratory support within 72 hours of birth or prior to discharge from the hospital (as defined above); death or mechanical ventilation or very high CPAP settings (\u0026ge;\u0026thinsp;8 cm water pressure and \u0026ge;\u0026thinsp;0.7 FiO\u003csub\u003e2\u003c/sub\u003e) in the first 72 hours of birth; and cause-specific mortality.\u003c/p\u003e\n\u003cp\u003eNewborn safety outcomes: neonatal sepsis in the first 7 days of birth; hypoglycaemia in the first 36 hours after birth.\u003c/p\u003e\n\u003cp\u003eNewborn health service utilization outcomes: admission to neonatal care unit in the first three days after birth; duration of birth hospitalization; and any parenteral antibiotic use in the first seven days after birth.\u003c/p\u003e\n\u003cp\u003eMaternal safety outcomes: maternal death; possible maternal bacterial infection during hospital admission(s); chorioamnionitis; and postpartum endometritis.\u003c/p\u003e\n\u003cp\u003eMaternal health service utilization outcomes: duration of hospital stay; any therapeutic antibiotic use; and any antibiotic use.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipant timeline\u003c/h2\u003e\n\u003cp\u003eThe participant timeline and follow-up process are summarized in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Screening, informed consent, and randomization will take place in study hospitals where the mother has presented and will give birth. Randomized women and their newborns will be followed up during the hospital stay and then to 28 days after birth. After randomization, study data will be recorded by trained research staff in participating hospitals. At the time of discharge, the woman will be advised to return to the study hospital or call the site investigators in the event of any adverse outcomes for her or her baby. All randomized participants (women and newborns) will have scheduled postpartum/postnatal follow-up visits conducted on day 7 and day 28.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eScreening, informed consent, and recruitment to the trial\u003c/h2\u003e\n\u003cp\u003ePregnant women admitted to the antenatal, labour ward or emergency admission area in the third trimester at participating hospitals will be routinely evaluated on arrival by obstetric care physicians. Women with clinical features or indications suggestive of preterm birth in the late preterm period will be informed of the study. Study staff (including research or clinical staff trained in study procedures) will conduct formal screening using a standardized screening form. The screening population is women who are between 34 weeks 0 days and 36 weeks 5 days and who are expected to deliver between 12 hours and 7 days. Screening will consist of three key activities to assess women for eligibility and trial entry: assessment of gestational age (34 weeks 0 days to 36 weeks 5 days), assessment if the delivery is likely between 12 hours and 7 days, and assessment for the presence of any exclusion criteria.\u003c/p\u003e\n\u003cp\u003eGestational age will be based on a best obstetric estimate combining information from the last menstrual period, regularity of cycles, and informed by the earliest ultrasound obtained in the pregnancy. Women will receive an ultrasound assessment for gestational age as part of this screening process if an obstetric ultrasound of reasonable quality for gestational age estimation has not been performed during the current pregnancy at least 2 weeks prior to the screening. In these screening ultrasounds, biometric measurement and gestational age assignment will be performed using INTERGROWTH-21st project biometry guidelines and fetal growth curves, respectively [\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e] (Additional file 3. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Prior to enrolling patients, all study sites received standardized training in the ultrasound evaluation of fetal biometry in the third trimester. Throughout the study, images will be reviewed regularly for quality assurance.\u003c/p\u003e\n\u003cp\u003eIf women are unable to complete the full screening and informed consent process (due to distress, or other reasons), they will not be recruited. All women will receive information about the trial in their language of choice via an information sheet. If willing to participate, the informed consent form will be signed by the participant and study staff.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eAllocation sequence generation\u003c/h2\u003e\n\u003cp\u003eParticipants will be randomly assigned to either dexamethasone-4x6 mg or betamethasobe-4x2 mg ACS regimen, or placebo in a 1:1:1 allocation as per a computer-generated randomization sequence, in balanced permuted blocks. The randomization sequence will be generated by a researcher external to the ACTION III trial. The assignment schedule will be stored at WHO headquarters in Geneva, Switzerland. All sites will receive treatment packs according to the randomization sequence, assembled in special dispensers. Facility study team members at participating sites will remove and open the next pack from the dispenser for allocation as per a set standard operating procedure.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eAllocation concealment and blinding\u003c/h2\u003e\n\u003cp\u003eAllocation concealment will be achieved by having identical treatment packs across the three arms. At the time of randomization, study staff will take the next sequentially numbered pack from the box (Additional file 3, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The IM injections will be administered by the hospital staff nurses according to study procedures.\u003c/p\u003e\n\u003cp\u003eParticipants, care providers, investigators, the WHO trial coordinating unit, and data collectors will be blinded to the group allocation. Each active drug will have its own saline placebo identically packaged to allow for blinding of the three arms. Betamethasone phosphate (4mg/ml as 1ml ampules) and its placebo (1ml normal saline) will be manufactured by Recipharm AB. Dexamethasone (4mg/ml as 1ml ampules) and its placebo (1ml normal saline) will be manufactured by Fresenius Kabi. All three arms will have identical packaging, appearance, labelling, and volumes to be administered.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003ch2\u003eEmergency unblinding procedures\u003c/h2\u003e\n\u003cp\u003eThe principal investigators at each site and a designated WHO project manager will receive the participants\u0026rsquo; treatment codes in the form of separate sealed envelopes that contain the treatment allocation for each participant, in case the code for a participant\u0026rsquo;s treatment needs to be broken urgently.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n\u003ch2\u003eRetention and follow-up procedures\u003c/h2\u003e\n\u003cp\u003eThe study team will request contact details (address, phone number, relatives) from randomized women, in order to facilitate communication at follow-up to 28 days after birth by home visit.\u003c/p\u003e\n\u003cp\u003eData collectors will make every reasonable effort to follow the woman and her newborn for the entire study period. After randomization, outcomes occurring in the facility (prior to discharge) will be captured by research study staff working in participating hospitals. At the time of discharge, the woman will be advised to return to the study hospital or call the site investigators in the event of any adverse outcomes for her or her baby.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n\u003ch2\u003eData management\u003c/h2\u003e\n\u003cp\u003eData will be managed centrally by a data management team, supervised directly by WHO project managers. The study statistician will be responsible for the development of the statistical analysis plan and reporting to the DSMB. A web-based, Good Clinical Practice (GCP) compliant data management platform (Kamolo, Centro Rosarino Estudios Perinatales (CREP) will be used, and be overseen by the site data managers. All data will be collected in study centres on paper case report forms (CRFs). Quality control will be performed at each site, and a validation system will be built into the data entry and management system to ensure consistency, accuracy and completeness of the data collected.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n\u003ch2\u003eConfidentiality\u003c/h2\u003e\n\u003cp\u003eTo ensure participant confidentiality, each participant will be identified by a unique ID number. The local trial register linking personal information and trial ID numbers, and all personal information of participants, will be kept separate from the CRFs. Trial documents will be kept securely under lock and key in the research offices and will not be accessible, other than to the researchers. Data will be entered by trial ID number in the password-protected data management system to which only trial staff will have access. The trial report will not contain the names of any participants, and after completion of the trial, the trial documents will be archived in accordance with institutional and national rules for clinical research archiving.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical methods\u003c/h2\u003e\n\u003cdiv id=\"Sec22\" class=\"Section3\"\u003e\n\u003ch2\u003eSample size\u003c/h2\u003e\n\u003cp\u003eIt is estimated that the prevalence of the primary composite outcome in the control arm will be between 10\u0026ndash;12% based on data from ACTION I [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e], ACTION II [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e], and the ALPS study [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] on late preterm births. A reduction of 20% is the minimal change deemed acceptable in the composite outcome, in order to change practice. Assuming a 2.5% loss to follow-up, a sample size of 4,500 women per arm in the three-arm trial will have at least 80% power and \u0026alpha; at 0.027 to account for multiple comparisons using Dunnett's method to detect a 20% reduction in the composite primary outcome.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n\u003ch2\u003eStatistical methods for primary and secondary outcomes\u003c/h2\u003e\n\u003cp\u003eThe primary intention-to-treat analysis will be based on all participants (i.e. newborns of randomized women, and women) with outcome data available. Data from participants who withdraw their consent for their data to be used will be excluded from the analysis and considered lost to follow-up.\u003c/p\u003e\n\u003cp\u003eComparative analyses between trial arms will consider multiplicity as both ACS arms use the same placebo arm as a comparator: confidence intervals for the intervention effect (e.g. risk ratios) will be computed to have a joint 95% coverage probability using Dunnett\u0026rsquo;s method [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe primary outcome and most secondary outcomes are binary variables. For these outcomes, the total number of observations, number of missing values and percentages will be reported per arm. Comparisons of outcomes between each intervention arm and the placebo arm, will be described using risk ratios. Risk ratios will be estimated by binomial generalised estimating equations with log links and robust standard errors to account for potential correlation of outcomes among babies born to the same mother. The primary analysis will include arm and site as fixed covariates, and a secondary analysis will also adjust for any baseline covariates for which there is an important imbalance at baseline. If the log binomial models fail to converge, then Poisson models with robust standard errors will be used.\u003c/p\u003e\n\u003cp\u003eFor continuous outcomes (duration of birth hospitalization for the mothers and the babies), the number of participants, missing values, minimum, maximum, means, and standard deviations by arm will be reported. Comparisons of each ACS dose arm against the placebo arm will be described as mean differences. Duration of birth hospitalization (continuous neonatal outcome) for all babies will be compared between arms as mean differences estimated using mixed linear models, including a maternal random effect to account for potential correlation of outcomes among babies born to the same mother. The median duration and Kaplan Meier curves will also be reported by arm.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n\u003ch2\u003eInterim analyses\u003c/h2\u003e\n\u003cp\u003eA first interim analysis by the Data Safety Monitoring Board (DSMB) is tentatively planned at 60% recruitment completion, however reporting on safety criteria (including serious adverse events) will occur quarterly. At this first interim analysis, the DSMB will look at the performance of both active arms combined, versus placebo. This is to minimize unnecessary exposure of additional women to the placebo (in case the combined arms are better than placebo). If the analysis reveals that the combined ACS arms are superior to placebo with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 (Peto\u0026rsquo;s rule), then the DSMB could recommend cessation of the placebo arm (after confirming that there is statistical evidence that at least one ACS arm is better than placebo with p\u0026thinsp;\u0026lt;\u0026thinsp;0.025, and for safety p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 for mortality. However, recommendations after the results of an interim analysis will not be guided only by statistical considerations, but also by practical issues (adverse events, unanticipated costs), as well as clinical considerations or external new information.\u003c/p\u003e\n\u003cp\u003eIn the event of both ACS regimens being superior to placebo, and based on a benefit-risk assessment, the DSMB could recommend a non-inferiority comparison between the two active arms..\u003c/p\u003e\n\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\n\u003ch2\u003eSubgroup analyses\u003c/h2\u003e\n\u003cp\u003ePre- and post-randomization subgroup analyses will be conducted for the primary endpoint. Pre-randomization subgroups include different indications for enrolment (i.e. rupture of membranes, preterm labour with intact membranes, planned termination), gestational age at enrolment (\u0026lt;\u0026thinsp;34 weeks 6 days, 35 weeks 0 days to 35 weeks 6 days, \u0026gt;\u0026thinsp;36 weeks 0 days), study site, and single vs multiple births. Post-randomization subgroups include gestational age at birth (preterm (\u0026lt;\u0026thinsp;37 weeks) vs. not preterm (\u0026ge;\u0026thinsp;37 weeks)), interval from time of IMP administration (i.e., first dose) to birth (0 to 12 hours, \u0026gt;\u0026thinsp;12 to 24 hours, \u0026gt;\u0026thinsp;24 hours to 7 days, \u0026gt;\u0026thinsp;7 days), use of tocolytics post-randomization, appropriate size for gestational age vs small for gestational age, and mode of birth (vaginal vs caesarean section).\u003c/p\u003e\n\u003cp\u003eStatistical tests for effect modification by the different factors mentioned above will be performed. While post-randomization subgroup analyses are at risk of bias, in the current trial we believe there are good scientific reasons to investigate these subgroups as there are plausible reasons why the treatment effects could be different. Also, these subgroups are clinically important, and are explicitly considered in the latest update of WHO\u0026rsquo;s ACS recommendations [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. Before conducting these post-randomization subgroup analyses, we will first examine whether the intervention has an effect on the stratifying variable.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\n\u003ch2\u003eTrial oversight\u003c/h2\u003e\n\u003cp\u003eMonitoring procedures have been prepared in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonised tripartite guideline for Good Clinical Practice E6 (R2). Monitoring activities will be conducted overall, per site and per hospital. Standard operating procedures will be prepared for all monitoring activities and will govern all monitoring procedures. Monitoring will be intensive throughout the trial recruitment period and will be conducted by independent trial monitors, principal investigators and co-investigators, and WHO trial coordinating unit (TCU) comprising WHO staff from two WHO Departments (Maternal, Newborn, Child, and Adolescent Health and Ageing, and Sexual and Reproductive Health and Research). Day-to-day oversight will be done by the trial steering committee comprising TCU and the principal investigators at each site. A technical Trial Advisory Group (external independent scientists with expertise in the area of preterm birth) led by an independent chair will advise the trial steering committee.\u003c/p\u003e\n\u003cp\u003eA study DSMB will comprise five members, including an independent chair, a statistician, and three technical experts familiar with the intervention, maternal and newborn health care, and clinical trial methodology. The DSMB will monitor adverse events on an ongoing basis to look for emerging safety risks and advise the trial coordinating unit (TCU) accordingly.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec27\" class=\"Section3\"\u003e\n\u003ch2\u003eEthical considerations\u003c/h2\u003e\n\u003cp\u003eThe trial protocol was reviewed and approved by the WHO Ethics Review Committee. All participating sites received approval from the relevant institutional scientific and ethical review committees in the respective country (as well as required permissions from the relevant national regulatory authorities) (Additional file 6). Any modifications to the protocol which may impact the conduct of the study, a potential benefit of the study participants, or may affect their safety, including changes in study objectives, study design, study population, sample sizes, study procedures, or other significant aspects will require a formal amendment to the protocol. Such amendments will be agreed upon by study co-investigators and submitted to WHO ethical review committee and participating institutional ethical review committees prior to implementation.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs the leading cause of neonatal and child mortality and morbidity, preterm birth is a critical global public health priority. Although \u0026gt;\u0026thinsp;80% of all preterm births occur in the late preterm period, there is still uncertainty on the balance of benefits and risks of using ACS in women at risk of a late preterm birth. This is evident from the divergent recommendations from different international guidelines.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] In WHO\u0026rsquo;s latest ACS recommendations, the Guideline Development Group noted that the ACTION III Trial would provide the necessary evidence to inform future recommendations [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe optimal dose of ACS that can confer benefit while minimizing unnecessary fetal exposure has not been studied extensively. This is particularly important, as ACS are a potent developmental modulator, and in-utero exposure (particularly for infants born in the late preterm or term period) has been linked with worse neurodevelopmental outcomes in childhood [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. There have been recent calls for trials on lower doses of steroids [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The BETADOSE trial in France was the first trial of a single half-dose versus full-dose betamethasone [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The betamethasone 4 x 2mg regimen planned in the ACTION III trial takes into consideration the pharmacokinetics of ACS and the need for a prolonged exposure to an adequate concentration over a longer period.\u003c/p\u003e \u003cp\u003eThe ACTION III trial will also clarify some of the uncertainties raised by the Antenatal Corticosteroids implementation trial (ACT) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] that was conducted in LMICs.\u003c/p\u003e \u003cp\u003eThe results of the ACTION III trial will contribute valuable information to bridge the evidence gap on the balance of benefits and risks of ACS in the late preterm period. Given the divergence in guidelines on ACS use in the late preterm period issued by various international and national bodies, in high- and low-income settings, the evidence from this trial will facilitate recommendations on the use of ACS in the late preterm period globally.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntenatal corticosteroids\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntenatal Corticosteroids Trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACTION\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntenatal Corticosteroids for Improving Outcomes in preterm Newborns\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData and Safety Monitoring Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGood clinical practice\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPIRIT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Protocol Items:Recommendations for Interventional Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrial Coordinating Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript is based on the current version of the protocol, version\u0026nbsp;1.16, which\u0026nbsp;was approved by the WHO Ethics Review Committee on 11\u003csup\u003eth\u003c/sup\u003e Apr 2023. Recruitment started on 15 July 2022 and is expected to be complete by December 2026.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Approved 03/03/2021, WHO Ethics Review Committee (20, Avenue Appia, Ch-1211, Geneva 27, Switzerland; +41 (0)22 791 1479; [email protected]), ref: 0003488).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e. The members of the WHO ACTION Trials Collaboration consent to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e.\u0026nbsp;Not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests.\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u003c/strong\u003e This trial is supported by the Bill and Melinda Gates Foundation (INV-005390).\u0026nbsp;The funder had no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e ADC, RB, OTO coordinated the writing of the study protocol, with input from the Technical Coordinating Unit (SG, TL, NM, MN, SR, JV), Principal Investigators and the Technical Advisory Group. All named members of the Collaboration had an opportunity to review and discuss the study protocol. WHO is the sponsor for the ACTION-III Trial, and takes overall responsibility for collection, management, analysis, and interpretation of data, writing of the report, and the decision to submit the report for publication. WHO can be contacted at [email protected]. The authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u003c/strong\u003e WHO gratefully acknowledges the contribution of the following experts:\u003c/p\u003e\n\u003cp\u003eTechnical Advisory Group: Elizabeth Molyneaux, Khalid Yunis, Hadiza Galadanci, Jeeva Sankar, Andrew Shennan\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData Safety and Monitoring Board: Betty Kirkwood, Jon Deeks, Justus Hofmeyr, Siddarth Ramji and Elizabeth Bukusi\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe WHO ACTION Trial Collaborators (listed alphabetically by family name):\u0026nbsp;\u003c/strong\u003eTemitope Adesiji Adegboyega, Ebunoluwa Aderonke Adejuyigbe, Olubukola Adeponle Adesina, Babalola Adeyemi, Salahuddin Ahmed, Francis Akinkunmi, Jalemba Aluvaala, Henry Anyabolu, Shabina Ariff, Sugandha Arya, Ibrahim Awowole, Adejumoke Idowu Ayede, Neelofur Babar, Sumitra Bachani, Rajiv Bahl, Abdullah H. Baqui, Harish Chellani, Saleha Begum Chowdhury, \u0026nbsp;Lynn M Coppola, Simon Cousens, Pradeep K Debata, Ayesha DeCosta*, Sangappa M Dhaded, Kasturi V Donimath, Adegoke Gbadegesin Falade, Shivaprasad S Goudar, Shuchita Gupta, George N. Gwako, Theresa Azonima Irinyenikan, Dennis Anthony Isah, Nigar Jabeen, Arshia Javed, \u0026nbsp;Naima T Joseph, Rasheda Khanam, John Kinuthia, Oluwafemi Kuti, Tina Lavin, Ahmed \u0026nbsp;R Laving, Sandhya Maranna, Nicole Minckas, Pratima Mittal, Diwakar Mohan, Sidrah Nausheen, My Huong Nguyen, Olufemi T Oladapo*, Olanike Abosede Olutekunbi, Rosena Olubanke Oluwafemi, Alfred Osoti, Yeshita V Pujar, Zahida P. Qureshi, Suman PN Rao, Sophie Sarrassat, M. A. Shahed, Mohammod Shahidullah, Lumaan Sheikh, Manjunath S Somannavar, Sajid Soofi, Jyotsna Suri, Sunil S Vernekar, Joshua P Vogel, Nitya Wadhwa, Prakash K Wari, Fred Were, \u0026nbsp;Blair J Wylie\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOhuma E, Moller A-B, Bradley E. (in press). National, regional, and worldwide estimates of preterm birth in 2020,with trends from 2010: a systematic analysis. Lancet 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevels \u0026amp; trends in child mortality. Report 2022. New York: United Nations Inter-Agency Group for Child Mortality Estimation (UNIGME); 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNatarajan G, Shankaran S. Short- and Long-Term Outcomes of Moderate and Late Preterm Infants. 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Geneva: World Health Organization. ; 2022. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/publications/i/item/9789240057296\u003c/span\u003e\u003cspan address=\"https://www.who.int/publications/i/item/9789240057296\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmitz T, Doret-Dion M, Sentilhes L, Parant O, Claris O, Renesme L, et al. Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. 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FIGO good practice recommendations on the use of prenatal corticosteroids to improve outcomes and minimize harm in babies born preterm. Int J Gynaecol Obstet. 2021;155(1):26\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/ijgo.13836\u003c/span\u003e\u003cspan address=\"10.1002/ijgo.13836\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedley N, Poljak B, Mammarella S, Alfirevic Z. Clinical guidelines for prevention and management of preterm birth: a systematic review. BJOG 2018;125(11):1361\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1111/1471-0528.15173\u003c/span\u003e\u003cspan address=\"10.1111/1471-0528.15173\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European consensus guidelines on the management of respiratory distress syndrome \u0026ndash; 2019 update. Neonatology. 2019;115(4):432\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1159/000499361\u003c/span\u003e\u003cspan address=\"10.1159/000499361\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan A-W, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1136/bmj.e7586\u003c/span\u003e\u003cspan address=\"10.1136/bmj.e7586\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. (jan08 15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePapageorghiou AT, Kemp B, Stones W, Ohuma EO, Kennedy SH, Purwar M, et al. Ultrasound-based gestational-age estimation in late pregnancy: International late pregnancy dating. Ultrasound Obstet Gynecol. 2016;48(6):719\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/uog.15894\u003c/span\u003e\u003cspan address=\"10.1002/uog.15894\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDunnett CW. 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J Obstet Gynaecol Can 2021;43(1):74\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.jogc.2020.02.127\u003c/span\u003e\u003cspan address=\"10.1016/j.jogc.2020.02.127\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary","content":"\u003cp\u003eAdditional file 6 is not available with this version. \u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"antenatal corticosteroids, late preterm birth, dexamethasone, betamethasone, low- and middle-income countries","lastPublishedDoi":"10.21203/rs.3.rs-3324018/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3324018/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePreterm birth complications are the leading cause of newborn and under-5 mortality. Over 85% of all preterm births occur in the late preterm period i.e., between 34 and \u0026lt;37 weeks of gestation. Antenatal corticosteroids (ACS) prevent mortality and respiratory morbidity when administered to women at high risk of an early preterm birth i.e. \u0026lt; 34 weeks’ gestation. However, the benefits and risks of ACS in the late preterm period are less clear; both guidelines and practices vary between settings. Emerging evidence suggests that the benefits of ACS may be achievable at lower doses than presently used. This trial aims to determine the efficacy and safety of two ACS regimens compared to placebo, when given to women with a high probability of late preterm birth, in hospitals in low-middle income countries (LMICs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWHO\u003cstrong\u003e \u003c/strong\u003eACTION III trial is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens: dexamethasone phosphate 4x6 mg q12h or betamethasone phosphate 4x2 mg q 12h. The trial is being conducted across seven sites in five countries- Bangladesh, India, Kenya, Nigeria and Pakistan. Eligible women are those with a gestational age between 34 weeks 0 days and 36 weeks 5 days, who have a high probability of preterm birth in next 12 hours to 7 days (up to 36 weeks 6 days gestation). The primary outcome is a composite of stillbirth or neonatal death within 72 hours of birth, or use of newborn respiratory support within 72 hours of birth or prior to discharge from hospital, whichever is earlier. Secondary outcomes include safety and health utilization measures for both women and newborns The sample size is 13,500 women.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThis trial will evaluate the benefits and possible harms of ACS when used in women likely to have a late preterm birth. It will also evaluate a lower-dose ACS regimen based on literature from pharmacokinetic studies. The results of this trial will provide robust critical evidence on the safe and appropriate use of ACS in the late preterm period internationally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eISRCTN11434567. Registered on 7 June 2021; \u003ca href=\"https://doi.org/10.1186/ISRCTN11434567\"\u003ehttps://doi.org/10.1186/ISRCTN11434567\u003c/a\u003e.\u003c/p\u003e","manuscriptTitle":"The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-30 20:49:52","doi":"10.21203/rs.3.rs-3324018/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-10-26T00:57:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-25T17:54:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-24T10:12:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2023-09-27T11:21:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a206bb55-16e8-4550-b1eb-9abd89bc6e31","owner":[],"postedDate":"October 30th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-15T15:04:40+00:00","versionOfRecord":{"articleIdentity":"rs-3324018","link":"https://doi.org/10.1186/s13063-024-07941-0","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-04-12 15:01:37","publishedOnDateReadable":"April 12th, 2024"},"versionCreatedAt":"2023-10-30 20:49:52","video":"","vorDoi":"10.1186/s13063-024-07941-0","vorDoiUrl":"https://doi.org/10.1186/s13063-024-07941-0","workflowStages":[]},"version":"v1","identity":"rs-3324018","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3324018","identity":"rs-3324018","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}