1. 1 Literature Review Peter R. McNally, DO, FACP, FACG University Colorado at Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. 2 Miehlke S, Madisch A, Bethke B, Morgner A, et al. Oral Budesonide for Maintenance Treatment of Collagenous Colitis: A Randomized, Double- Blind, Placebo-Controlled Trial. Gastroenterology. 2008;135:1510-1516. Dresden, Germany

3. 3 Introduction Collagenous colitis is an idiopathic disorder characterized by chronic diarrhea, a normal macroscopic colonoscopy, but characteristic mucosal changes on biopsy. Collagenous colitis is an idiopathic disorder characterized by chronic diarrhea, a normal macroscopic colonoscopy, but characteristic mucosal changes on biopsy. Incidence “microscopic colitis” 8.6 per 100,000 in US 1985-2001 with secular ↑ 20 per 100,000 @ 2001 Incidence “microscopic colitis” 8.6 per 100,000 in US 1985-2001 with secular ↑ 20 per 100,000 @ 2001 ♀ >> ♂ (ratio 2-4:1) ♀ >> ♂ (ratio 2-4:1) Incidence increases with age, arthritis, autoimmune disorders, celiac disease and use of NSAID’s Incidence increases with age, arthritis, autoimmune disorders, celiac disease and use of NSAID’s Schiller LR. Diagnosis and management of microscopic colitis syndrome. J Clin Gastroenterol. 2004;38(5 Suppl):S27-30. Pardi DS, Loftus EV, Smyrk TC, et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut. 2007;56:504-8.

4. 4 Courtesy, Leslie Sobin, MD. Armed Forces Institute Pathology. Wash, DC. Collagenous Colitis Treatment Acute: Anti-diarrheal agents are helpful for 1/3 of patients. Bismuth subsalicylate and 5- aminoslaysilates benefit some. Budesonide is effective acute treatment. Chronic: No medical treatment has been tested for safety or efficacy in maintenance trials Chande N, McDonald JW, MacDonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003575 Introduction Collagenous colitis: thickened sub-epithelial collagen band > 10 μm (normal 0-3 μm). Note: the diameter of an RBC is 6–8 µm.

5. 5 Aim To evaluate the efficacy of long-term maintenance therapy with oral budesonide (Entocort CIR capsules, AstraZeneca, Lund, Sweden) for maintenance of clinical remission of collagenous colitis, including effects on histology and HRQOL. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

6. 6 Study Design: Study Population Enrollment from 38 centers in Germany Enrollment from 38 centers in Germany Men and women > 18 yrs Men and women > 18 yrs Symptomatic and biopsy proven collagenous colitis Symptomatic and biopsy proven collagenous colitis Inclusion Criteria Inclusion Criteria – > 3 watery/loose stool per day (> 4 of 7 previous days) (> 4 of 7 previous days) – Diarrhea symptoms > 4 weeks duration Exclusion Criteria Exclusion Criteria – Infectious cause for diarrhea – Inflammatory Bowel Disease, Celiac disease, Malignancy – Prior Large bowel surgery – Current Rx: 5-ASA, NSAIDs, >165mg ASA/day – Alcohol/drug abuse or Pregnancy Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

7. 7 Study Design Collagenous colitis + Diarrhea Budesonide (B) 9mg/d for 6 weeks Clinical Remission Placebo (P) 6mg/d for 6 mo Budesonide (B) 6mg/d for 6 mo Open-Label Induction Phase Double-Blind Maintenance Phase

8. 8 Study Design Primary End Point: Relapse Rate @ T 6wk & 6 mo Primary End Point: Relapse Rate @ T 6wk & 6 mo – Definition of Relapse: > 3 stools/day on 4 consecutive days Secondary End Points Secondary End Points – Time to relapse – Proportion of patients in remission Time 6wk, 2, 4, 6 mo Time 6wk, 2, 4, 6 mo – HRQOL outcomes – ∆ Histology Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

9. 9 Study Tools Health Related Quality of Life(HRQOL) SF-36 Health Related Quality of Life(HRQOL) SF-36 – 4 physical health domains (controls > 50.2) – 4 mental health domains (controls > 51.2) – Measurements taken @ T0, 6wk, 2,4,6 mo Short Inflammatory Bowel Disease Questionaire (sIBDQ) Short Inflammatory Bowel Disease Questionaire (sIBDQ) Safety Assessments (Global Tolerability) Safety Assessments (Global Tolerability) – “Very Good,” “Good,” “Moderate,” or “Bad” Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

10. 10 Colonoscopy & Histology Evaluations Colonoscopy and biopsy Time 0 n = 48 Time 6 mo n = 25 (17B, 8P) Only if in remission Histology Evaluation Measurement of subepithelial collagen band Measurement of subepithelial collagen band Inflammation: absent, mild, moderate, severe Degeneration surface epithelium: absent or present Trichrome stain, blue band of thickened sub-epithelial collagen and mild lympocytic inflammation. Courtesy, Shalini Tayal, MD. Denver Health Med Center. Denver, CO. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

11. 11 Flow of Patients Through Study 167elgible pts clinical and histologic diagnosis of collagenous colitis 48 pts started 6 wk budesonide induction 46 pts randomized (23 budesonide, 23 placebo) 25 pts completed study (17 budesonide, 8 placebo) 21 pts withdrawn AE (3 budesonide, 1placebo) Relapase (3 budesonide, 1 placebo) 2 pts failed budesonide induction 119 pts excluded or refused Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

12. 12 Demographics & Clinical Characteristics VariableN=48 Mean age, yrs (range) 57.5 (34-78) Women, n (%) 35 (75) Stool consistency, n (%) watery watery loose loose mixed mixed26(54)11(23)7(15) Abdominal Pain n (%) 8(17) Weight Loss, n (%) Mean wt loss prev 6 mo kg (range) Mean wt loss prev 6 mo kg (range)24(50%)6.7(2-17) Duration of diarrhea before diagnosis, months (range) 27 (1-66) Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

13. 13 Results HRQOL SF-36 Scores HRQOL SF-36 Scores SF-36 T0 Study PtsControl SF-36 T0 Study PtsControl Physical domain39.550.2p<0.05 Physical domain39.550.2p<0.05 Mental Domain44.151.2p<0.05 Mental Domain44.151.2p<0.05 SF-36 T6wk Rx Study Pts = Control SF-36 T6wk Rx Study Pts = Control Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

14. 14 Results: Kaplan-Meier curves of patients with relapse of collagenous colitis during maintenance therapy with Budesonide or Placebo Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. P =.022

15. 15 Results: Histologic Findings Variable Time 0 48 pts T 6mo 23 pts Remission Mucosal erythrema 11/48 (23%) None (17 B/8 P) Histologic Improvement 14/15 B 5/8 P Baseline Collagen band 13.3 μ m B 13.2 μ m P ∆↓↓ p=.005 ∆↓ p=.043 Baseline inflammation ∆↓8/10 (80%) ∆↓ 5/6 (83%) Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

16. 16 Results: Proportion of patients in clinical remission on maintenance budesonide or placebo Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. P=.007P=.017P=.008 % In Remission

17. 17 Adverse Events Induction Phase Budesonide 9mg/d N=48 Pts with AEs, n (%) 5 (10) Freq of AEs (n) Headach(2), hearing (1), URI(1) dental infection (1)

18. 18 Adverse Events Maintenance Phase Budesonide 6mg/d N=23PlaceboN=23 Pts with AEs, n (%) n (%) 8 (35) AE-related withdrawal n (%) 3 (13) 1 (4) AE- discontinuing Dizzy (1), Sleep (1), muscle pain (1), ulcer(1), skin erythrema (1) Thrombosis (1), URI (1) AE-continuing Headache (2), UTI (1), URI (1), back pain (1), abd pain (1), wt gain (1), HTN (1) Abd pain(3), bloating(2), URI(1), nausea(1), back pain(1), dental pain (1), skin erythrema(1), MVA (1)

19. 19 Conclusions: 1. Budesonide 9 mg daily for 6 weeks was effective in inducing remission (46/48, 98%) in most patients with collagenous colitis. 2. Budesonide 6 mg daily for 6 months was effective in maintaining remission. Clinical relapse rates were much lower in the budesonide group compared to placebo 6/23 (26%) vs. 15/23 (65%), respectfully. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

20. 20 Conclusions: 3. No serious side effects occurred during maintenance treatment with budesonide. Tolerability of budesonide was considered “very good” or “good” in 61% at 6 month. 4. Long term maintenance (6 mo) therapy with budesonide (Entorcort CIR capsules) was well tolerated and prevented clinical relapse in 75% of patients with collagenous colitis. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

21. 21 Reviewer Comments Dr. Miehlke and colleagues have shown: 1. Acute treatment with budesonide 9 mg daily is effective in Collagenous Colitis, n= 46/48 or 98% response. 2. Chronic (6 mo) maintenance with budesonide 6 mg daily is superior to placebo by clinical symptoms and QOL, with 80% vs. 20% (B vs. P) remission at 6 months. 3. Chronic (6 mo) budesonide is safe and “well” tolerated by most patients with Collagenous Colitis. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

22. 22 Reviewer Comments Miehlke, et al, do not answer the following questions? 1. Why histologic improvement in inflammation is seen just a commonly in placebo as budesonide treatment groups? 2. What is the inciting factor of this disorder? 3. What is the natural history of collagenous colitis? 4. Does duration of disease impact acute and durable long term response to budesonide? Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.