Introduction:
It is difficult to choose trial enrollment criteria that will yield a robust treatment effect. To address this problem, we developed a novel trial design that restricts enrollment criteria to the patient subgroup most likely to show benefit, if an interim analysis indicates futility in the overall sample. Future recruitment, and the population in which the primary hypothesis is tested, is limited to the selected subgroup.
Hypothesis:
A design with adaptive subgroup selection increases the power of endovascular stroke studies.
Methods:
We ran simulations to compare the power of the adaptive design with that of a traditional design. Trial parameters were: type I error 0.025, type II error 0.1, analysis after 450, 675 and 900 patients (interim and final analyses in IMS III). Outcome data were based on 90 day mRS scores observed in IMS III among patients with a vessel occlusion on baseline CTA (n=289). Subgroups were defined a priori according to vessel occlusion (ICA ± distal occlusion vs M1 vs M2-4), onset-to-randomization time (early vs late), and treatment allocation (IA+IV vs IV alone). The treatment effect in the overall cohort was a mean mRS improvement of 0.15 (2.41 for IV+IA vs 2.56 for IV alone; SD 1.45). The subgroup treatment effects were: early ICA = 0.54, late ICA = 0.60, early M1 = 0.33, late M1 = 0.07, early M2-4 = -0.66, and late M2-4 = -0.35.
Results:
The traditional design showed a treatment benefit in 31% of simulations. The adaptive design showed benefit in 91%, failed to show benefit after enrollment of the maximum sample in 1%, and stopped early for futility in 8% of simulations. The adaptive trial stopped early for benefit in 84% of simulations. Due to early stopping, the mean number of patients randomized is 590±140 with the adaptive design vs 900 with a traditional design. Of the adaptive trial simulations that showed benefit, 91% occur after subgroup selection. The subgroup selected most often (31% of all simulations) includes early and late ICA patients.
Conclusions:
A trial with adaptive subgroup selection can efficiently test the effect of endovascular stroke treatment. Simulations suggest that with this design, IMS III would have 91% power and would typically stop early after interim analysis shows benefit in a patient subgroup.
Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov