Increasing trial efficiency by early reallocation of placebo nonresponders in sequential parallel comparison designs: Application to antidepressant trials

Abstract

Background

The sequential parallel comparison (SPC) design was proposed to improve the efficiency of psychiatric clinical trials by reducing the impact of placebo response. It consists of two consecutive placebo-controlled comparisons of which the second is only entered by placebo nonresponders from the first. Previous studies suggest that in antidepressant trials, nonresponse to placebo can already be predicted after 2 weeks of follow-up. This would allow to reduce the first phase of the SPC design to further increase its efficiency.

Purpose

To compare the sample size requirements of an 8-week randomized controlled trial (RCT₈) and alternative SPC designs with equal or longer total follow-up duration (SPC₂₊₆, SPC₄₊₄, and SPC₆₊₆).

Methods

Scenarios for response and dropout rates were defined. Sample sizes to achieve 80% power were determined for the various designs. Three treatment functions assumed either a smaller, equal, or larger effect at the early stage of the trial as compared with that at the end. Two dropout models described either predominantly early or linearly increasing dropout, and dropout was considered as nonresponse. The relative efficiency of the different designs was evaluated across these scenarios and for a specific scenario based on empirical antidepressant trial data.

Results

The different SPC designs (i.e., SPC₂₊₆, SPC₄₊₄, and SPC₆₊₆) were generally more efficient than the RCT₈ design when the treatment effect at the early stage of the trial was equal or larger than the effect at the end. In this case, the advantage of the SPC designs increased in the presence of dropout. The SPC₂₊₆ design was usually more efficient than the SPC₄₊₄ design and was relatively less affected by dropout when it occurred predominantly early. For the scenario that was based on antidepressant trial data, the SPC₂₊₆ and SPC₄₊₄ designs required 51% and 53% fewer patients than the RCT₈ design.

Limitations

A limited variety of scenarios was evaluated. Parameter values resembled those observed in antidepressant trials.

Conclusions

This study suggests that SPC designs are highly efficient alternatives to a conventional RCT in indications where placebo response is high and substantial treatment effects are established after a relatively short follow-up period (i.e., after the first SPC design phase). We conclude that SPC designs can reduce sample size requirements and increase success rates of antidepressant trials.