Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the "ProSPoNS" Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. DISCUSSION: This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low-middle-income countries. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019.

Challenges in Implementation of the ANISA Protocol at the Odisha Site in India.

BACKGROUND: The Aetiology of Neonatal Infection in South Asia (ANISA) study is being carried out at 5 sites across Bangladesh, India and Pakistan, generating in-depth information on etiologic agents in the community setting. Pregnancies are identified, births are registered and young infants are followed up to 59 days old with regular assessments for possible serious bacterial infection following a generic protocol. Specimens are collected from suspected cases. This article describes the challenges in implementing the generic ANISA protocol and modifications made to accommodate the Odisha site, India. CHALLENGES: Primary challenges in implementing the protocol are the large geographic area, with a population of over 350,000, to be covered; assessing young infants at home and arranging timely transport of sick young infants to study hospitals for physician confirmation of illness; and specimen collection and treatment. A large workforce is deployed in a 3-tier system in the field, while clinical, microbiology, laboratory and data management teams collaborate dynamically. Mobile phones with text message capability, integration with the Odisha State government's health system, involvement of local communities and strict monitoring at different levels have been critical in addressing these challenges. CONCLUSION: This article describes the challenges and modalities adopted to collect complex and accurate data on etiology, timing of disease and associated factors for community-acquired neonatal infections. Attention to local culture and customs, training and employing community level workers and supervisors, involving existing government machinery, using technology (cell phones), and uninterrupted systematic monitoring are critical for implementing such complex protocols that aim to collect population-based data to drive policy.