Background/Aims
The use of adaptive designs has been increasing in randomized clinical trials. Sample size re-estimation is a type of adaptation in which nuisance parameters are estimated at an interim point in the trial and the sample size re-computed based on these estimates. The Secondary Prevention of Small Subcortical Strokes (SPS3) study was a randomized clinical trial assessing the impact of single vs. dual antiplatelet therapy and control of systolic blood pressure to a higher (130-149 mmHg) vs. lower (<130 mmHg) on recurrent stroke risk in a two-by-two factorial design. A sample size re-estimation was performed during the SPS3 study resulting in an increase from the planned sample size of 2500 to 3020, and we sought to determine the impact of the sample size re-estimation on the study results.
Methods
We assessed the results of the primary efficacy and safety analyses with the full 3020 patients and compared them to the results that would have been observed had randomization ended with 2500 patients. The primary efficacy outcome considered was recurrent stroke, and the primary safety outcomes were major bleeds and death. We computed incidence rates for the efficacy and safety outcomes and used Cox proportional hazards models to examine the hazard ratios for each of the two treatment interventions (i.e. the antiplatelet and blood pressure interventions).
Results
In the antiplatelet intervention, the hazard ratio was not materially modified by increasing the sample size, nor did the conclusions regarding the efficacy of mono vs. dual-therapy change: there was no difference in the effect of dual vs. mono therapy on the risk of recurrent stroke hazard ratios (n=3020 (95% CI): 0.92 (0.72, 1.2) p=0.48; n=2500 (95%CI): 1.0 (0.78, 1.3), p=0.85). With respect to the blood pressure intervention, increasing the sample size resulted in less certainty in the results, as the hazard ratio for higher vs. lower systolic blood pressure target approached, but did not achieve, statistical significance with the larger sample (n=3020 (95% CI): 0.81 (0.63, 1.), p=0.089; n=2500 (95% CI): 0.89 (0.68, 1.17), p=0.40). The results from the safety analyses were similar with 3020 and 2500 patients for both study interventions. Other trial-related factors, such as contracts, finances and study management were impacted as well.
Conclusions
Adaptive designs can have benefits in randomized clinical trials, but do not always result in significant findings. The impact of adaptive designs should be measured in terms of both trial results, as well as practical issues related to trial management. More post-hoc analyses of study adaptations will lead to better understanding of the balance between the benefits and the costs.