1. When Should a Clinical Trial Design with Pre-Stratification be Used? Group 1

2. Stratification Why? – Achieve balance between groups on factors associated with the response (prognostic variables) How? – Strata created based on prognostic factors Pre-Stratification – Stratification before treatment allocation; accounted for in analysis Post-Stratification – Treatment allocation without strata; stratification in analysis

3. When to Pre-Stratify Aims: – Reduction in variability (balance of prognostic factors between treatment groups) – Increase in power Conditions: – Known salient prognostic variables Ex: Multiple study sites – Allows for dropping or adding sites during trial (FDA.gov) Ex: Gender, age groups, etc. – Focus on few prognostic variables – More important in smaller study size Kernan et al 1999

4. Example: CARP Trial

5. The Study Study Question – Is coronary re-vascularization appropriate in patients with stable coronary artery disease prior to an elective major vascular surgery? Study Design – Randomized, multi-center phase III trial – Intervention Coronary re-vascularization prior to elective surgery No coronary re-vascularization prior to elective surgery – Primary endpoint = long-term mortality Pre-stratification: – Center (18 VA Medical Centers) – Prognostic factor: Type of elective vascular surgery (intraabdominal or infrainguinal)

6. On Stratification Center 1 Vascular Intervention Planned Intrabdominal Infrainguinal Pre-Strata 1: Center Pre-Strata 2: Vascular Surgery Randomize Yes No Yes No Intervention: Re-vascularization

7. Results of Stratification

8. Why not post-stratify? Higher risk for imbalance in vascular surgery type getting different study intervention – Could skew the primary outcome Center 1 Outcome Intrabdominal Infrainguinal Pre-Strata: Center Post-Strata: Vascular Surgery Randomize Yes No Intervention: Re-vascularization

9. Problems with Pre-Stratification Requires baseline values for prognostic variables prior to randomization Precise stratum definition can be difficult More administrative work Small gain in power for large trial Can diminish power if too many strata

10. Summary When Should a Clinical Trial Design with Pre- Stratification be Used? – Multi-center studies – Smaller sample size with known prognostic factors – Known prognostic factors that may be difficult to post-stratify