Cyrus Mehta Ph.D. and Lingyun Liu Ph.D Cytel Inc., Cambridge MA

1. Adaptive Designs to Demonstrate Risk Reduction in Cardiovascular Outcome TrialsA Case Study of the EXAMINE Trial Cyrus Mehta Ph.D. and Lingyun Liu Ph.D Cytel Inc., Cambridge MA

2. The EXAMINE Trial • Multicenter randomized double blind placebo controlled study of Alogliptin a DPP4 inhibitor • Designed to rule out excess risk of CV outcomes in very high risk T2DM patients • Primary Endpoint: composite of first occurrence of CV death, MI or stroke (MACE) • FDA Guidance: estimate upper bound of 95% RCI for the hazard ratio of Alogliptin/Placebo • if < 1.8: submit pre-marketing NDA for alogliptin • if < 1.3: CV safety demonstrated FDA and Industry: September 23, 2014

3. EXAMINE: Group Sequential Design • O’Brien-Fleming spending function • Sample size: 5400 • Events: 150 for 1.8 and 650 for 1.3 • Enrolment 2 years • Trial duration 4.25 years • 94% power for 1.8 for true HR=1 • 91% power for 1.3 for true HR=1 • Only 53% power to claim superiority if true HR=0.85 FDA and Industry: September 23, 2014

4. EXAMINE: Study Results • Total enroll: 5383 • IA1: 83 events • Upper bound of RCI: 1.51 • Submitted NDA • IA2: 550 events • HR: 0.96 • Upper bound RCI: 1.17 • Stopped to claim non-inferiority • White et. al. published in NEJM Trial could have continued to 650 events in hopes of showing superiority Why stop at 550 and accept a non-inferiority claim? FDA and Industry: September 23, 2014

5. Trial was underpowered for Superiority Sample size requirements for a trial powered to show superiority (assumes 2 years accrual and 3 additional years of follow-up) • Deterrents to an up-front superiority design • Don’t know what HR to target • HR = 0.8 unlikely • HR > 0.85 leads to very large trial with high risk of failure FDA and Industry: September 23, 2014

6. The Risks of Powering Up-Front for Superiority • SAVOR-TIMI Trial (NEJM 2013) • Designed up front for superiority • Planned for 1040 events and 16,500 patients • 85% power to detect HR=0.83 • O’Brien-Fleming boundary at 50% information • After enrolling 16,492 patients with 2.1 years median follow-up and 1222 MACE events, the trial failed to show superiority • Could have designed a smarter trial! FDA and Industry: September 23, 2014

7. Less risky to allow switching from NI to Superiority objective at interim analysis • Power for non-inferiority with 650 events and 5400 patients • At interim analysis (IA-550), re-power for superiority by increasing the number of events and sample size provided: • NI criterion is met (RCI bound < 1.3) • CP(Sup) is in a “promising zone” FDA and Industry: September 23, 2014

8. Decision Rules at Interim Analysis FDA and Industry: September 23, 2014

9. The Path to an Adaptive Switch FDA and Industry: September 23, 2014

10. Criteria for adaptive increase of events and sample size FDA and Industry: September 23, 2014

11. Zones for Decision Making to Claim Superiority after NI Boundary is Crossed Stop and claim NI: CP(sup)<20% Unfavorable Zone: 20% ≤CP(sup)<50% Carry on with no change Promising Zone: 50% <CP(sup)≤90% Double the events and sample size Favorable Zone: CP(sup)>90% Carry on with no change FDA and Industry: September 23, 2014

12. No adjustment necessary for adaptation Since promising zone starts at 50% conditional power, no special adjustment needed for the adaptive increase in events (Chen, DeMets and Lan, 2004) Thus one can use the classical RCI for a group sequential superiority trial where D is the number of MACE events at the final analysis (here 650) FDA and Industry: September 23, 2014

13. Results: If IA-550 is in Promising Zone FDA and Industry: September 23, 2014

14. Operating Characteristics if HR=0.85 • NI claim is assured • Sup claim has good prospects too • 40% chance at IA with 550 events • 0.12x0.37= 4% chance at 650 events (no adaptation) • 0.11*0.96=11% chance at 1300 events (adaptation) • If adaptation occurs, 96% chance of showing Sup FDA and Industry: September 23, 2014

15. Operating Characteristics if HR=1 • NI claim has at least 90% power (per design) with 76% chance of early stop • Very little (<2%) chance of showing superiority • Only 2% chance of expanding the trial by doubling sample size and events FDA and Industry: September 23, 2014

16. Operational Considerations • All design details are included in DMC charter • DMC buys into design at the kick-off meeting, but reserves right to exercise clinical judgment • Although the trial is expanded only if the IA at 550 events shows promise of superiority: • Actual interim decision should only be conveyed on need to know basis (to drug supply and IVRS teams) • Investigators may be told only that this adaptive design has a maximum sample size of 13,000 patients and possibility of showing superiority • Double blind design also important to avoid bias FDA and Industry: September 23, 2014

17. Concluding Remarks • No anti-glycemic agent has shown protection to CV risk • Huge up-side to being the first on the market • Traditional superiority design requires: • large up-front commitment of resources • considerable optimism about underlying HR • SAVOR-TIMI example underscores the risks • Start with modest expectations and expand only if interim results are promising FDA and Industry: September 23, 2014