AFRINEST(1) 2015.

Methods	This study is an individually‐randomised, multicentre, open‐label equivalence trial conducted from 2011 to 2013. The study took place at five sites, one each in DR Congo and Kenya, and three in Nigeria (Ibadan, Ile‐Ife, and Zaria). Community health workers identified cases of suspected neonatal sepsis which was confirmed by a treatment nurse. A treatment nurse at an outpatient health facility gave injections in DR Congo and Kenya, and a community health extension worker gave injections at the homes of enrolled infants in Nigeria. The treatment nurse gave the first dose every day when an oral antibiotic was scheduled. The mother gave the second dose of oral antibiotic per day, every day. Community health workers or community health extension workers, and their supervisors received training in the WHO and UNICEF's 'Caring for the Newborn at Home' course. Study nurses and their supervisors attended a 'Young Infant IMCI' course.
Participants	Inclusion criteria: age 0 to 59 days, any sign of clinical severe infection (stopped feeding well (defined as poor feeding on observation), movement only when stimulated, severe chest indrawing, and axillary temperature ≥ 38·0°C or < 35·5°C), parents did not accept or could not access referral level care, parents gave consent to participate in the study. Exclusion criteria: critically ill ‐ characterised by the presence of any of the following signs: unconsciousness, convulsions, unable to feed at all, apnoea, unable to cry, cyanosis, dehydration, bulging fontanelle, major congenital malformations inhibiting oral antibiotic intake, active bleeding requiring transfusion, surgical conditions needing hospital referral, and persistent vomiting defined as vomiting after three attempts to feed the baby within 30 min, very low weight (< 1500 grams at the time of presentation), and hospital admission for illness in the past two weeks or previously enrolled in the study
Interventions	The reference treatment regimen was injectable gentamicin (4 mg/kg in the first week of life 7.5 mg/kg thereafter) and procaine benzylpenicillin (50,000 units/kg) for seven days which was compared with three simplified antibiotic regimens: injectable gentamicin and oral amoxicillin (75 mg/kg if < 2 kg and 100 mg/kg if > 2 kg) treatment for seven days; injectable procaine benzylpenicillin–gentamicin for two days, then oral amoxicillin for five days; and injectable gentamicin once per day for two days and oral amoxicillin for seven days
Outcomes	Primary outcome: treatment failure by the day eight post‐enrolment visit. Treatment failure was defined as any one of: death, clinical deterioration, no improvement in clinical condition by day four, infant not cured by day eight, or development of a serious adverse event other than death that was thought to be related to the study antibiotics. The secondary outcomes were death between days 9 and 15 after enrolment, relapse, and adherence to the allocated treatment between days one and eight.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We stratified young infants aged 0 to 59 days with clinical signs of severe infection by age (0 to 6 days and 7 to 59 days) and we individually randomly assigned them within these strata to receive one of the four treatment regimens...an off‐site person at WHO, who was not associated with the study, prepared randomisation lists. They generated randomisation lists for each site, for each of the two age strata, in a 1:1 ratio in blocks of eight using Stata 10." Comment: there was appropriate random sequence generation
Allocation concealment (selection bias)	Low risk	Quote: "We sealed treatment allocation codes on a folded piece of card in two sets of sequentially numbered opaque colored envelopes, one color for each age stratum...The treatment allocation code remained concealed until after informed consent was obtained and the young infant enrolled in the study." Comment: there was appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Treatment allocation was open to the parents and the treating health workers because it was deemed to be unethical to give placebo injections to young infants." Comment: the nature of the intervention made blinding of participants and personnel not feasible, but the outcome is not likely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Outcome assessment nurses were unaware of the infant's treatment allocation." Comment: personnel assessing the outcomes were sufficiently blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Among all enrolled infants, 3364 (94%) fulfilled our treatment adherence and follow‐up assessment criteria for inclusion in the per‐protocol analysis" Comment: treatment adherence and follow‐up assessment criteria was similar across all four treatment regimens (93%, 93%, 96%, 95%)
Selective reporting (reporting bias)	Low risk	Comment: The trial was registered with a clinical trials registry. In addition, the study protocol was published in Pediatric Infectious Disease Journal in 2013. The authors reported all outcomes described in the protocol. Australian New Zealand Clinical Trials Registry number: ACTRN12610000286044
Other bias	High risk	Response bias ‐ comment: all injectable medications were delivered by study personnel but some or all doses of oral medications were administered by caregivers and adherence was based on caregiver report. There is a high risk of responder bias affecting only the arms in which oral medications were administered.