Table 5.

Sample sizes for active-comparator non-inferiority study designs. The hypothesis is that the new modulator is no more than a ‘small amount’ less efficacious than an active comparator, quantified by a non-inferiority (NI) margin

	Previously observed FEV1 treatment effect*: comparator–placebo, (95% CI)*	FEV1 SD of the change in FEV1 % predicted*	% of Lowest treatment effect to preserve	NI margin†	Sample size per group‡
Scenario A: non-inferiority study vs an active comparator which has efficacy comparable with lumacaftor–ivacaftor
	3.0% (1.6 to 4.4)	7.3	75%	0.75×1.6=1.2%	778
Scenario B: non-inferiority study vs an active comparator which has efficacy comparable with ivacaftor
	10.6% (8.6 to 12.6)	7.0	50%	0.50×8.6=4.3%	56

*Treatment effects and SDs approximated from the 6-month changes in FEV₁ observed in previous trials.^{16 21}

†The NI margin is derived based on preserving a percentage of the lowest possible treatment effect observed in the placebo-controlled trial, as captured by the lower bound of the 95% CI. NI margins must be negotiated with regulators and ensure that a clinically meaningful effect size will be maintained.

‡Assuming there is truly no difference between the new modulator and the active comparator, sample size estimates are generated with 90% power to ensure that the lower limit of a one-sided 97.5% CI will be above the NI margin.