Sample size determination in group-sequential clinical trials with two co-primary endpoints.

Area of Science:

• Biostatistics
• Clinical Trial Design
• Pharmaceutical Statistics

Background:

• Group-sequential designs are efficient for clinical trials, allowing early stopping.
• Trials with multiple co-primary endpoints present unique challenges in sample size determination.
• Existing methods may not adequately address the complexities of dual endpoints in sequential testing.

Purpose of the Study:

• To develop and evaluate sample size determination methods for group-sequential trials with two co-primary endpoints.
• To compare two distinct decision-making frameworks for claiming treatment benefit based on dual endpoints.
• To provide practical guidance and illustrative examples for sample size calculations in such designs.

Main Methods:

• Derivation of power and sample size formulas for two decision frameworks.
• Framework 1: Simultaneous superiority at an interim analysis.
• Framework 2: Superiority at any interim analysis (non-simultaneous).

Main Results:

• Sample size and power behaviors are evaluated across various design elements.
• A real-world example demonstrates the application of the proposed sample size methods.
• Impact of sample size recalculation on power and Type I error rate is assessed.

Conclusions:

• The proposed methods offer flexible approaches to sample size determination for dual-endpoint trials.
• Understanding the implications of different decision rules is vital for efficient trial design.
• Sample size recalculation strategies can be evaluated for their impact on trial integrity.