Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the S/ F ratio. Because of the ceiling effect in oxyhaemoglobin saturation, S/ F ratio ceases to reflect pulmonary oxygenation function at high SpO2 values. We found that the correlation of S/ F with the reference standard (PaO2 / FIO2 ratio) improves substantially when excluding SpO2> 0.94 and refer to this measure as S/ F94 . Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that S/ F94 is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using S/ F94 . We demonstrate that S/ F94 is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power.