gms | German Medical Science

Introduction: Formal proof of efficacy of a new drug requires that in a prospective experiment superiority over placebo or superiority or at least non-inferiority to an established standard is demonstrated. Traditionally one primary endpoint is specified. Nevertheless, in some more complex diseases, e.g. Alzheimer’s disease, treatment success has to be based on the assessment of co-primary endpoints where both need to be “significant” as a pre-requisite for study success. No adjustment of the study-wise type-1-error is needed, but the sample size usually needs to be increased to maintain the pre-specified power. Frequently, studies with dual primary endpoints that use an at-least-one concept ^{1 2} have been proposed in this context. Here, study success is claimed if superiority for at least one of several primary endpoints is demonstrated and an appropriate adjustment to control the study-wise type-1-error is required. However, the dual primary endpoint concept has the disadvantage that study success can be claimed if one endpoint shows significant superiority while a detrimental effect is observed for the other.

Methods: In line with Röhmel’s strategy³, we discuss an alternative approach with additional constraints to the dual primary endpoint concept to assure a statistically and clinically consistent strategy for decision-making. First, a certain minimal requirement for both primary endpoints must be met, e.g., non-inferiority, before superiority has to be demonstrated for at least one. We compared our decision strategies with the dual primary endpoint concept regarding increased costs (in terms of power and sample size) in a simulation study. Simulation scenarios included various treatment effects and two correlations for three different sample sizes with Alzheimer’s disease as motivating example.

Results: Our simulations illustrated that if the treatment effects are as planned, additional constraints to the dual primary endpoint concept lead to statistically and clinically consistent decisions on study success. Application of the additional constraints also improves interpretation while the loss in power is acceptable. Moreover, this approach allows flexible modeling of the minimum expectations for both primary endpoints while leading back to the co-primary endpoint concept.

Discussions and conclusion: There might be other clinical scenarios next to Alzheimer’s disease where our approach might be rational. For instance, we considered oncologic trials with time-to-event endpoints as a further potential field of application. When defining, e.g. progression-free and overall survival as primary endpoints in an oncologic trial, one could require non-inferiority for both and superiority in at least one. The approach implies a more detailed discussion and pre-definition of more aspects at the planning stage of a trial, including considering the minimum expectations for both primary endpoints. Therefore, statistically and clinically consistent decisions on study success can be made in several clinical scenarios leading to improved certainty and interpretability regarding results of clinical trials.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.

This contribution has already been published:

• already (partially) presented at GMDS 2022
• planned as tandem lecture with CEN-IBS 2023