GLOBVAC-Global helse- og vaksin.forskn

Almost 2.7 of the 5.9 million deaths in children under 5 years of age occur in the first month of life (the neonatal period) and about 75% of these deaths occur in the first week. More than 70% of the neonatal deaths occur in Africa and South East Asia. Severe infections like pneumonia and sepsis contribute 25% of all infant deaths and are a major cause of hospitalisation. Despite antimicrobial therapy, the case fatality risk, especially among the young infants (i.e. those less than two months of age) remains high. Effective interventions that can be added to the standard antibiotics and supportive therapy are required to improve survival. Oral zinc is a promising intervention in severe childhood infection. In a previous study, we demonstrated that oral zinc added to standard treatment resulted in a reduced risk of treatment failure and possibly fewer deaths. This single randomised controlled trial does not, however, suffice to alter treatment recommendations. The current randomised double-blind placebo-controlled trial is being done as a collaborative project between Translational Health Science and Technology Institute in India, University of Bergen and the Innlandet Hospital Trust in Norway, and Tribhuvan University in Nepal. We estimate whether zinc given twice daily to young infants (3 days up to 2 months of age) treated in hospital with antibiotics for clinical severe infection reduces their risk of dying. The intervention (zinc/placebo) will be given for a total duration of 14 days. The ongoing study intends to enrol nearly 4,000 young infants across different hospitals in New Delhi where clinical severe infection contributes importantly to infant mortality. We started enrolling eligible young infants into the study in February 2017 and have till date enrolled more than half of the planned study population. The results will be available when the study infants have been enrolled, completed their course of zinc or placebo tablets and then completed their study period of 12 weeks from the day of enrolment. The GLOBVAC-funded project ended in 2019; with additional funding from the Centre of Intervention Science in Maternal and Child Health (www.cismac.org), we have prolonged the data-collection period until March 2021, and hope to procure additional funding to enable us to reach the projected sample size. If this large, multicentre study shows that zinc enhances survival of young infants with clinical severe infection, its use as an adjunct to standard therapy could lead to substantial reductions in infant mortality, particularly in settings where resources are limited, antibiotic resistance is common and second line antibiotics may not be readily available. Further, an evaluation of the incremental cost-effectiveness of zinc supplementation is planned to further inform policy. Our engagement with policy makers, academic organisations and the WHO will be important because, if indeed adjunct therapy with zinc enhances the survival among young infants with clinical severe infection, this management approach can be quickly translated into guidelines and child health promotion strategies.

i. Enhanced expertise of the different multidisciplinary trial teams: quality assurance, project and data management ii. Strengthened clinical research capacity in the participating hospital sites by training future clinical scientists and public health researchers iii. Established a mentorship program whereby the study team members benefit from the knowledge and expertise available across the partnering and CISMAC institutions iv. Foster collaborations with other groups nationally and globally v. If the results of this study are consistent with our earlier trial (Bhatnagar et al, Lancet, 2012), there would be substantially strengthened evidence for recommending zinc as an adjunct to standard therapy for clinical severe infection in young infants. If we succeed in translating our findings into recommendations, this study will contribute importantly to enhance child survival in low- and middle-income countries.

Scientific basis: The prognosis of sepsis in early infancy is poor. While appropriate antibiotics are available in many hospitals in India and Nepal, second-line antibiotics may be unavailable in peripheral health facilities or are prohibitively expensive . It is important to develop inexpensive, effective and accessible interventions that can be added to standard therapy for severe infections to improve clinical outcomes and to reduce case fatality. In a recent randomised controlled trial in India, we fou nd that daily oral zinc treatment had an efficacy of 40% against treatment failure in 7-120 days old infants with probable serious bacterial infection. The trial was not powered to evaluate the effect of the intervention on the risk of case fatality, and we accordingly propose this new multi-centre trial. Study design: Individually randomized double-blind placebo-controlled hospital-based trial. Study participants and site: Young infants aged 1 day up to 2 months hospitalized in secondary referral level hospitals of India and Nepal with very severe disease as defined by IMNCI. Intervention: Daily oral administration of 10 mg of elemental zinc along with standard antibiotic therapy. Comparator: Placebo along with standard antibiotic therapy. Outcomes: Pri mary: (i) case fatality. Secondary: (i) primary treatment failure (ii) time from enrolment to cessation of symptoms and signs of very severe disease (iii) time to failure of primary treatment (iv) time to hospital discharge (v) survival and function of p eripheral blood mononuclear cells and innate immunity (vi) an evaluation of the incremental cost effectiveness of zinc supplementation will be conducted to inform policy. Relevance for programs and public health: If zinc treatment of young infants with ve ry severe disease reduces the risk of death it should be incorporated into global and national guidelines.