Table 2.

Planned and adaptive hypotheses, effect sizes, and power for varying levels of estimated active-control effectiveness in an example trial comparing and experimental HIV PrEP agent to an active control (oral HIV PrEP). Four methods of computing the required benefit over placebo (Δ) are shown, including (1) Δ_pian which is defined to preserve 50% of the active-control benefit at the planned level of effectiveness, (2)Δ_Est which preserves 50% of the estimated active-control benefit at the observed level of effectiveness, (3)Δ_Min which preserves both 50% of the estimated benefit at the observed level of effectiveness and an MCID (defined here as 0.90), and (4) Δ_Max which preserves 50% of the estimated benefit at the observed level of effectiveness and places a maximum on the Nl margin. Also shown are two methods for specifying the alternative hypothesis ξ), the first fixing Ω. based on the pre-planned alternative ξ=0.80, and the second method holding ξ constant at 0.80. Bolded values are fixed by design and determine the adaptive margins, hypotheses, and effect sizes. All values are relative risks exceptp and power. The pre-planned sample size is 231 HIV-infection events.

						Fixed target benefit over placebo				Fixed target benefit over active control
	Active-control effectiveness†	Assured active-control benefit -LCL,s(RRp/c)‡	Required benefit over Placebo -Δ	Adaptive Null / Nl margin -δa	Proportion of Benefit Preserved -ρ	Fixed/planned target benefit over placebo -Ω	Adaptive Alternative* -ξa	Effect size ξa/δa	Power	Effective target benefit over placebo -Ω	Fixed alternative -ξ	Effect size ξ/δa	Power
Preserve planned benefit Δ=ΔPlan	Higher than planned	1.89	0.82	1.54	0.32	0.53	1.00	0.65	0.90	0.42	0.80	0.52	1.00
	As planned	1.50	0.82	1.23	0.50	0.53	0.80	0.65	0.90	0.53	0.80	0.65	0.90
	Lower than planned	1.17	0.82	0.95ϕ	1.33	0.53	0.62	0.65	0.90	0.69	0.80	0.84	0.26
Preserve proportional benefit Δ=ΔEst	Higher than planned	1.89	0.73	1.37	0.50	0.53	1.00	0.73	0.66	0.42	0.80	0.58	0.98
	As planned	1.50	0.82	1.23	0.50	0.53	0.80	0.65	0.90	0.53	0.80	0.65	0.90
	Lower than planned	1.17	0.93	1.08	0.50	0.53	0.62	0.57	0.99	0.69	0.80	0.74	0.63
Preserve proportional benefit and MCID Δ=min(ΔMCID, ΔEst), ΔMCID=0.90	Higher than planned	1.89	0.73	1.37	0.50	0.53	1.00	0.73	0.66	0.42	0.80	0.58	1.00
	As planned	1.50	0.82	1.23	0.50	0.53	0.80	0.65	0.90	0.53	0.80	0.65	0.90
	Lower than planned	1.17	0.90	1.05	0.69	0.53	0.62	0.59	0.98	0.69	0.80	0.76	0.54
Preserve proportional benefit and limit the maximum margin ΔMax= min(1.23/LCL95(RRp/c), ΔEst)	Higher than planned	1.89	0.65	1.23	0.67	0.53	1.00	0.82	0.34	0.42	0.80	0.65	0.90
	As planned	1.50	0.82	1.23	0.50	0.53	0.80	0.65	0.90	0.53	0.80	0.65	0.90
	Lower than planned	1.17	0.93	1.08	0.50	0.53	0.62	0.57	0.99	0.69	0.80	0.74	0.63

^†Planned effectiveness is based on 60% adherence, higher than planned is based on 70% adherence, and lower than planned is based on 50% adherence.

^‡The "assured benefit" is the Lower Confidence Limit(LCL) of the 95% confidence interval surrounding the relative risk (RR) of HIV infection comparing placebo to active-control (oral PrEP), as estimated by the meta-regression model for oral PrEP effectiveness as a function of drug adherence and sex.

^*When adherence is as planned, the alternative is also as planned (fixed at 0.80).

^ϕA margin less than one indicates that super superiority is required. In this example, in order to maintain the pre-planned benefot over placebo, the experimental therapy must be at least 5% better than the active control.