Phase III, Multicentre, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy of Probiotic Supplementation for Prevention of Neona

Summary (layman): Neonatal infections are a major cause of sickness and death in infancy in the developing countries. Treatment with antibiotics has limitation as the bacteria have become resistant and there is dearth of new antibiotics. At present there is lack of knowledge about how to prevent the disease. Current trial aims to find out if feeding probiotics daily for 30 days during the first month of life would prevent these infections. Remaining healthy in the first month is important as it allows the newborns to grow to become healthy adults. The study would be coordinated by three research organizations and implemented at six sites in India. 6500 Newborn infants weighing less than 2500gms would be allocated to either the probiotics or a placebo group without the study participants' or researchers' knowledge of the group assignment. They would be fed the assigned drug and followed up in their homes regularly upto 60 days by trained field workers (daily in the first week, biweekly during 2-4 weeks of life, and weekly during the second month) to find out if they fell sick. Sick infants would be referred/taken to study physician for examination, testing and treatment. All study related information would be captured on Tablets/hand held devices and sent to a central location for analysis. After completion of the study the data would be analysed to see whether there were less infections/sepsis cases in the group where infants were fed with probiotics as compared to the other group. If the results favour the probiotics it could be used as a new method of preventing neonatal infections in the developing countries. This would benefit millions of newborns who are currently dying due to infections.

Neonatal infections (pneumonia, septicaemia, meningitis) are responsible for more than a quarter of the 1 million neonatal deaths every year in India(1). Low Birth Weight (LBW) is a very important indirect cause of death in neonates, accounting for 40% to 80% of neonatal deaths (2-3). Management of neonatal sepsis with antibiotics faces the problem of drug resistance and immune-modulation/immune-potentiating with the use of probiotics may prove to be an option. Available evidence suggests a beneficial effect of probiotics treatment on reducing the incidence and all -cause mortality due to NEC (4-5.). In our pilot study supplementation with probiotics VSL#3 in LBW infants was associated with a non-significant overall 21% reduction in the risk of suspected sepsis (PSBI). In the post-hoc analyses using physician's diagnosis of sepsis as the outcome measure, there was a 33% overall reduction in risk of sepsis. However, in the un-prespecified sub-group of infants weighing 1.5-1.99 kg, there was a 100% reduction, with no cases observed in the group receiving probiotic supplementation (6). Following on from the evidence on VLBW and premature infants and based on the positive results of the above mentioned pilot study, we propose to test the hypothesis, with sufficient power and a precise definition of the outcome measure to conclusively evaluate the role of probiotics among LBW infants in a multicentre double blind placebo controlled trial.

Impact summary: Please refer to the Pathways to Impact document. Prevention of neonatal sepsis with probiotics, as proposed in this proposal, is directly linked with improved health, quality healthy growth and development of infants in the context of Sustainable Development goals. The primary beneficiaries from this research would be the newborn population of India and other LMICs. Taking into consideration the leads from the pilot study completed by ICMR, a 30% prevalence of LBW in India and 30% mortality due to sepsis in newborns, it may be expected that even a modest decline in the incidence of sepsis due to the proposed intervention with probiotics could avert thousands of neonatal deaths. Saving newborn lives, the proposed intervention would allow thousands of babies to grow and become productive human beings, thus contributing to the nation's health & wealth. When produced at large scale the interventional product would be a cost-effective intervention for a major public health problem. To facilitate this, Government of India would sign a Memorandum of understanding with the manufacturer Zydus Cadila Healthcare to continue manufacturing the product in India for the public health system. It would be distributed to Indian public Health system through the government channels. Translation of research evidence into policy would be possible in 2-3 years time after completion of the study.The scientific community - academicians, researchers, practitioners all would benefit from the new evidence of knowledge/ modality for prevention of neonatal sepsis which is a major cause of neonatal morbidity and mortality. Households with low-birth weight babies, especially in developing countries where the disease burden is high, would be the ultimate beneficiaries from this novel prevention modality.