Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial & Role of Central Endpoint Adjudication

Abstract

Abstract Background: Despite progress in reducing Infant mortality in India, neonatal mortality decline is slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming prevention of neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention, including probiotic supplementation. This article communicates the decision by ProSPoNS trial investigators to establish a Central Endpoint Adjudication committee as an addendum to the published protocol in 'Trials 2021.' Methods: In the pursuit of clarity regarding the primary outcome of Sepsis/PSBI in a clinical trial, a crucial decision was reached during the investigators' meeting at MGIMS Sevagram on 17th-18th August 2023. The unanimous consensus was to explicitly define "Physician diagnosed sepsis" as the primary study outcome, encompassing Sepsis/PSBI. This alignment aimed to synchronize the primary objective and outcome with the stated hypothesis, necessitating the establishment of a Central Endpoint Adjudication (CEA) process across all six trial sites. To enact this, the CEA committee, chaired by an external Subject Expert and comprising Site Principal Investigators, a Trial Statistician, and a Microbiologist, will employ four criteria to determine 'Physician diagnosed sepsis' for each sickness event in a study participant. These criteria include Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms, and the Clinical course during the event, including antibiotic usage. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. Results: The challenges faced in the trial implementation, such as complex multi-centric design, heterogeneity / extreme variation across sites, inconsistency with definition of sepsis in the neonatal/young infant population, remote vs. on-site training/monitoring during the Covid-19 Pandemic have been described and potential solutions to some of the challenges in clinical trials suggested. Conclusions: The decision to utilize the guidance of a Central Endpoint Adjudication Committee has been suggested as a way forward in the ProSPoNS and other multicentre complex clinical trials. Trial registration: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.