PROPS 1986.

Study characteristics
Methods	RCT, double‐blind, placebo controlled. Participants randomised to penicillin prophylaxis (105) or placebo (110) by central blocked randomisation.
Participants	Children aged 3 to 36 months of age from 23 centres within the USA were randomised. Children were included if they were free from symptoms of infection at enrolment and excluded if they were receiving long‐term antibiotics, transfusion therapy or had a known allergy to penicillin.
Interventions	Children received penicillin V (125 mg twice daily, oral), or placebo (vitamin C 50 mg twice daily) immediately on entry to the trial. Trial terminated 8 months early after an average of 15 months follow‐up.
Outcomes	The incidence of documented bacterial infection of S pneumoniae or any other organism.
Notes	There were no documented declarations of interests among the primary researchers.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The PROPS (Penicillin Prophylaxis Study) data coordinating center generated the randomization numbers for each clinical site and with the help of the program office, directed patient ‐ entry assignments by means of telephone contact. Sealed envelopes that were stored at the clinical centres were available as a back up for randomization when telephone contact was not possible, but they were rarely used. The randomization schedules were prepared with the use of blocked randomization within each clinic to ensure balance in numbers between two groups."
Allocation concealment (selection bias)	Low risk	A central co‐ordinating centre directed participant entry assignment over the telephone. Sealed envelopes were also held at the clinical centres in case the central office could not be reached, to maintain allocation concealment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The participants and centre personnel were blinded to allocation, and placebo tablets looked almost identical to penicillin.
Incomplete outcome data (attrition bias) All outcomes	High risk	219 children with homozygous SCD were randomised, however, 4 children were removed due to revision of genotype; these children had no severe infections but were not included in subsequent analyses. The baseline characteristics of the children in each group, including history of palpable spleen or infection, were similar. The trial was terminated early due to extreme results. Given this, there is a possibility that the reported results may be over‐estimated.
Selective Reporting (Reporting Bias)	Low risk	Both the primary and secondary outcomes were adequately reported "the trial was terminated early, after the occurrence of 15 episodes of pneumococcal sepsis 13 in the placebo group and 2 in the penicillin group". Additionally, baseline characteristics of both study groups are adequately reported.
Other potential Sources of Bias	Low risk	None known.