Randomization and blinding
The randomization schedule is provided by the Clinical Epidemiology and Biostatistics Unit at the Murdoch Children’s Research Institute, Melbourne, Australia. Randomization with balanced variable block sizes is used, stratified by study center, gestational age (22–25 weeks’ vs. 26–27 weeks’ completed gestation), prior surfactant therapy, and mode of respiratory support at randomization (mechanical ventilation via an endotracheal tube vs. non-invasive respiratory support).When eligibility of an infant is confirmed, and prospective consent obtained, the infant is assigned to either receive surfactant plus budesonide, or surfactant alone, using a web-based randomization system with an allocation ratio of 1:1. A checklist on the website is used to confirm eligibility prior to randomization. Multiple births where more than one infant is eligible are randomized individually. A sealed opaque envelope at the study site is identified by the unique study ID generated from the web-based server (Parents/caregivers, direct healthcare providers, outcome assessors, data analysts, and trial investigators are blinded to the randomization group. Our experience is that it is virtually impossible to distinguish between the control and intervention study drugs, although there theoretically may be a subtle difference in the appearance of the surfactant with budesonide admixed. Additionally, the volume of the study drug to be administered is 0.5 mL/kg greater in the active treatment arm. To maintain blinding, the study drugs will be prepared by an independent intervention team whose members are not directly involved in the clinical care of the infant, and not involved in data collection or outcome assessments for the study. Data on the dose and type of intervention, as well as other data required by hospital pharmacies, will be recorded by the intervention team on allocation cards and stored in a secure lockbox only accessible by hospital pharmacists. In addition, after preparation of the intervention, the contents of the syringe will be covered using a stick-on label to obscure the volume and appearance to the bedside clinical staff. The pharmacy departments of each participating center and the Clinical Epidemiology and Biostatistics Unit will be the only other personnel aware of the allocated study intervention; they also will not be involved in data collection or outcome assessments for the study. Pharmacies will maintain a logbook of allocated study drugs and doses.Neither the PLUSS Trial Steering Committee nor site researchers will be aware of the allocated interventions and will not be permitted access to this information until trial completion.