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

Abstract

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

Targeting the Toll-like receptor pathway as a therapeutic strategy for neonatal infection

“…Clinical studies and interventional trials are key to explore novel ways to prevent and treat infection and related morbidity in the neonatal population. A trial testing the efficacy of a probiotic containing a mix of eight strains of bacteria in sepsis prevention in neonates is currently recruiting participants (256). Another new trial is assessing the benefits of multistrain probiotic products in the prevention of multidrug-resistant bacterial infection.…”

Study protocol for economic evaluation of probiotic intervention for prevention of neonatal sepsis in 0–2-month old low-birth weight infants in India: the ProSPoNS trial

“…The ProSPoNS trial3 proposes to evaluate the role of probiotics in prevention of neonatal infections (sepsis) among the vulnerable group of low-birth weight infants contributing the highest rates of morbidity and mortality. A larger sample size and precise outcome measures differentiate this trial from the earlier conducted pilot study that showcased a 21% non-significant decline in morbidity due to neonatal sepsis in the intervention arm.…”

“…A larger sample size and precise outcome measures differentiate this trial from the earlier conducted pilot study that showcased a 21% non-significant decline in morbidity due to neonatal sepsis in the intervention arm. Considering the 30% prevalence of low-birth weight (LBW) in India and 30% mortality due to neonatal sepsis, even a small decline in the incidence of sepsis would translate to a large number of new born lives saved 3…”