How long should young infants less than two months of age with moderate-mortality-risk signs of possible serious bacterial infection be hospitalised for? Study protocol for a randomised controlled trial from low- and middle-income countries.

Background: Hospitalisation and a seven-day injectable antibiotics course are recommended by the World Health Organization (WHO) to treat suspected clinical neonatal sepsis / possible serious bacterial infection (PSBI). Some infants presenting with PSBI signs associated with a moderate risk of mortality may only need a two-day hospitalisation followed by outpatient care treatment with oral antibiotics to complete seven days of antibiotics. Methods: A multi-centre, individually randomised, open-label trial will be conducted in seven sites in six countries: Bangladesh, Ethiopia, India (two sites), Nigeria, Pakistan and Tanzania. A common protocol will be used with the same study design, including the participants, intervention, comparison, outcomes, quality control, and analysis procedures. 0-59 days old infants presenting with moderate-mortality risk signs (low body temperature (<35.5°C), movement only when stimulated, stopped feeding well) or two or more signs of clinical severe infection (CSI) will be assessed and pre-enrolled. After 48 hours of hospital stay, clinically stable infants with a negative C-reactive protein test will be randomised either to hospital discharge on oral amoxicillin (intervention) or continued hospitalisation (control) arm. The intervention arm will receive oral amoxicillin for five days, whereas the control arm will receive injection gentamicin plus injection ampicillin for five more days plus supportive therapy if needed. We plan to enrol 5250 eligible young infants, 2625 infants in each of the two study arms. An experienced, well-trained independent outcome assessor will visit all enrolled cases on days 4, 8 and 15 after the initiation of treatment to assess the study outcomes in both intervention and control arms. The primary outcome of poor clinical outcome defined as death between randomisation and day 15 of initiation of treatment, deterioration during the 7-day treatment period, or persistence of the presenting sign of CSI at the end of the 7-day treatment period will be compared to assess if an early discharge and outpatient treatment leads to superior or at least non-inferior clinical outcome than continued inpatient treatment. The harmonisation of activities, including methods and processes, will be carried out diligently. Central training will be conducted by the WHO coordinating team, a central data coordination centre to collate all data, standardisation exercises for all clinical signs and internal and external monitoring. All the selected sites have extensive research experience. Through regular online and physical meetings, data-based monitoring, and physical site visits by WHO monitors, quality assurance and harmonisation will be ensured. This trial has been approved by the WHO and local site institutional ethics committees. Discussion: If the results show that young infants with moderate-mortality risk PSBI signs can be safely and effectively treated on an outpatient basis after a shorter hospital stay, it will reduce the burden on the hospitals, potentially reduce nosocomial hospital infections and increase access to treatment for families with poor access to health facilities. It may also reduce the health system costs (human and materials) and allow the overburdened hospitals to pay more attention to critically ill young infants. In addition, this evidence will contribute to making a case for reviewing the WHO PSBI guideline. Registration: International Standard Randomised Controlled Trial Number, ISRCTN16872570.