1. 1 Lotronex: Clinical Trials Thomas Permutt Division of Biometrics II with David Hoberman, Ph.D. Zili Li, M.D.

2. 2 Statistical Issues Risk –What is the risk? –How does it change over time? –Are there risk factors? Benefit –Populations with big benefit? –Populations with little benefit?

3. 3 What Is the Risk? Complications of constipation –11/11,000 in controlled trials –3/3,000 on placebo –Stopping rules 10% dropout on alosetron 1% on placebo Ischemic colitis

4. 4 Ischemic Colitis at 3 months 20 studies –>100 patients each –11,000 patients on alosetron –12 studies with no cases Overall rate 2/1000 Study 20 has 10 of 18 cases –late study: better ascertainment? –rate 5/1000

5. 5 Change over Time (12 months) Little information past 6 months –700 alosetron patients at month 7 –12,000 at month 1 –1 case of ischemic colitis (placebo)

6. 6 Change over Time (6 months) Cumulative risk keeps rising Risk per unit time may decrease Cumulative risk is important Most cases in month 1, but 30% of exposure also in month 1

7. 7 Risk Factors for Ischemic Colitis Known in broad population None identified with alosetron Everyone is at risk

8. 8 Benefit: Populations with Big Benefit? Urgency Quality of Life (Productivity)

9. 9 Urgency Responder: –Start above 5 days per week –End below 2 days per week (3 months) Studies 3001, 3002 –alosetron 32% –placebo 19% Studies 30011, 30012 (more severe) –alosetron 50% –placebo 29%

10. 10 Productivity Treatment difference 1 hour per week Less than spontaneous improvement in placebo

11. 11 Populations with Little Benefit Stool consistency hard or lumpy Stool frequency <2 per day May also be at higher risk

12. 12 Clinical Trials: Conclusions Risk –What is the risk? Complications of constipation –no excess over placebo, but … –possible dropouts before complications Ischemic colitis –excess over placebo –2 to 5 per 1000 over 3 months –How does it change over time? (ischemic colitis) Cumulative risk rises Hazard may decrease somewhat after 1 month Very little information past 6 months –Are there risk factors? No. Benefit –Populations with big benefit? Yes, e.g., urgency –Populations with little benefit? Yes, e.g. hard stools