Small Bowel Toxicity of Nonselective NSAIDs Revealed by Capsule Endoscopy: Results From a Pivotal Clinical Trial

1. Small Bowel Toxicity of Nonselective NSAIDs Revealed by Capsule Endoscopy: Results From a Pivotal Clinical Trial Glenn M. Eisen, M.D., M.P.H. Associate Professor of Medicine Oregon Health and Science University, Portland, Oregon

2. NSAIDs and Small Intestinal Damage 10 * 8.4% 8 NSAID group (n = 249) Control group (n = 464) 6 % of Subjects With Small Intestinal Ulcers 4 2 0.6% 0 Nonspecific ulcers *P < 0.001 Allison, et al. N Engl J Med. 1992;327:749–754.

3. Patients NSAID Use P Value OR AOR Controls 34% – – – UGIB 60% < 0.001 3.0* 3.2 LGIB 60% < 0.001 3.0* 2.6* NSAID Use Is Associated With Both Upper and Lower GI Bleeding • Case-controlled study of upper GI bleeding (UGIB) and lower GI bleeding (LGIB) • Use of NSAIDs within 1 week of admission was documented * P < 0.05 OR = odds ratio; AOR = OR adjusted for age, race, and gender. Wilcox CM, et al. Dig Dis Sci. 1997;42:990–997.

4. Rates of Serious Lower GI Events per 100 Patients-Years in Patients Receiving Rofecoxib vs Naproxen Relative Risk (95% CI) 0.46(0.22-0.93) P = 0.03 1.0 0.89 0.8 Rofecoxib 0.6 % of Patients with Serious Lower GI Events per 100 Patient-Years (n = 4,047) 0.41 Naproxen 0.4 (n = 4,029) 0.2 0 Laine, et al. Gastroenterology. 2003;124:288-292.

5. CLASS: Decreases in Hct ≥ 10% and/or Hgb > 2 g/dL 10 Celecoxib Diclofenac Ibuprofen 8 * 5.7 * 4.5 6 * 3.7 * 4.4 % of Patients 4 2.4 2.0 2 0 All Patients Patients Without Complications *P < 0.05 vs celecoxib FDA Arthritis Advisory Committee Meeting. February 7, 2001. Gaithersburg, Maryland, USA.

6. Hypothesis The combination of a non-specific NSAID + PPI will be associated with a rate of small bowel mucosal breaks that is significantly higher than the rate for placebo or for a COX-2 specific inhibitor

7. Inside the M2A Capsule

8. NSAID-Induced Lesions

9. Study Design Start study drug Naproxen 500 mg BID plus omeprazole 20 mg QD 2-week run-in period Healthy Subjects Celecoxib 200 mg BID Placebo 2-week Tx period Screening Randomization Final M2A video capsule (final) M2A video capsule (baseline)

10. Primary End Point (mITT) Mean Number of Small-Bowel Mucosal Breaks (Grades 2, 3, 6, and 7) P < 0.001 P < 0.001 3 2.99 2 Mean # of SB Mucosal Breaks (Grades 2, 3, 6, and 7) 1 0.32 0.11 0 Celecoxib (n = 115) Naproxen + PPI (n = 111) Placebo (n = 113) P = 0.042 Goldstein J, Eisen G, Gralnek I, Clin Gastroenterol and Hepatol Feb 2005

11. Capsule Endoscopy StudySecondary End Point (mITT) Incidence of Small Bowel Mucosal Breaks *Across three treatments corresponding to general association of the Cochran-Mantel-Haenszel test having stratified by site

12. Conclusions • As in the upper GI tract, inhibition of COX-1 by naproxen and not celecoxib translates into significantly different rates of mucosal injury in the small bowel • These findings extend the original COX-1 sparing hypothesis beyond the upper GI tract and into the small bowel

13. Conclusions (2) • Use of NS-NSAIDs can potentially lead to mucosal lesions, gastrointestinal bleeding beyond the ligament of Treitz • PPI use does not protect against NSAID induced damage to the small/large intestine • Capsule endoscopy provides a noninvasive assessment of the small bowel, which may be clinically useful in patients at risk for small bowel injury