What s New in IBS? Rome III Criteria for IBS

Transcription

1 What s New in IBS? American College of Gastroenterology Kansas City MO, August 22, 2015 Brian E. Lacy, Ph.D., M.D., FACG Professor of Medicine Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology & Hepatology Dartmouth-Hitchcock Medical Center Lebanon, NH Rome III Criteria for IBS Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Longstreth GF, et al. Gastroenterology. 2006;130: Copyright 2015 American College of Gastroenterology 1

2 Managing IBS: What Do Your Patients Want? They want you to listen Understand their history (symptoms, work, home) Education about their condition Address questions or concerns Address uncertainty of IBS Reassurance A positive diagnosisi Review results with patients Symptom improvement Treatment Depends on Severity of IBS Psychological treatments Goal: improved function Continuing care + Follow-up visit Manage stress Drug therapy + Diet, lifestyle advice Positive diagnosis Explain, reassure Severe (25%) Moderate (35%) Mild (40%) Copyright 2015 American College of Gastroenterology 2

3 IBS: New Guidelines Bulking Agents for IBS-C: Systematic Review and Meta-analysis RCTs N Fiber Response* Placebo RR of Unimproved Symptoms (95% CI) NNT (95%CI) Overall % 43% 0.86 ( ) 10 (5-100) Ispaghula % 36% 0.83 ( ) 7 (3-50) Bran % 46% 0.90 ( ) *Improved or resolved symptoms. Insoluble fiber was not more effective and sometimes worsened symptoms Soluble fiber improved global symptoms 4 out of 6 bran studies of poor quality CI = confidence interval; NNT = number needed to treat; RCTs = randomized, controlled trials; RR = relative risk Moayeddi P, Quigley EE, Lacy BE, et al. Am J Gastroenterol 2014; 109: Copyright 2015 American College of Gastroenterology 3

4 IBS & Probiotics: Global Symptoms IBS & Antidepressants Copyright 2015 American College of Gastroenterology 4

5 IBS Treatments: Diet Food & IBS Symptoms: The patient s perspective 60% of patients report worsening of symptoms after meals 1 Survey of 1,242 IBS patients the following interventions improved symptoms 2 small meals (69%) avoiding fat (64%) increasing fiber (58%) avoiding milk products (54%) 1 Chey et al, Am J Gastroenterol 2002; 2 Halpert et al, Am J Gastroenterol 2007 Copyright 2015 American College of Gastroenterology 5

6 Elimination diet IgG elimination diet Low carbohydrate IBS & Diet Low fructose/fructan Low gluten Low FODMAP Copyright 2015 American College of Gastroenterology 6

7 IBS & Low Gluten R, DB, PC, re-challenge study 34 IBS patients (Rome III); celiac excluded Prior improvement in Sx on gluten-free diet 16 gm of non-fermentable gluten substitute/day vs. 16 grams of gluten Primary endpoint: adequate symptom relief Gluten-group had less improvement in Sx than those on gluten-free (68% vs. 40%; p =.001) Biesiekierski et al, Am J Gastro 2011 IBS & Low Gluten Diet Biesiekierski et al, Am J Gastro 2011 Copyright 2015 American College of Gastroenterology 7

8 IBS and Gluten-free Diet 45 Pts with IBS-D (43 women); 4-weeks Gluten-free diet (23) vs. Gluten-diet (22) Genotype analysis performed Stool frequency, intestinal transit and intestinal permeability measured Results: Gluten diet was associated with increased SB permeability, especially in HLA- DQ2/8 positive patients Vazquez-Roque et al, Gastroenterology 2013; 144: IBS & Low FODMAP Diet Fermentable Oligo-, Di-, Monosaccharides And Polyols Excess Fructose Fructans Sorbitol Raffinose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners, artificially sweetened gums Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes Shepherd SJ, et al. J Am Diet Assoc. 2006;106: Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6: Gibson PR, et al. J Gastroenterol Hepatol. 2010;25: Copyright 2015 American College of Gastroenterology 8

9 IBS & Low FODMAP Diet: Or, what is there left to eat? Lean proteins Gluten-free breads, rolls, pasta Rice, corn, oat products Quinoa Safe fruits and vegetables: Snow peas, bok choy, mandarin oranges IBS: Prospective study to Evaluate Low FODMAP diet 82 consecutive IBS patients (NICE criteria) Detailed symptom and dietary evaluation 9 month evaluation performed in UK Individual symptoms and global IBS symptoms measured 39 in the standard diet group 42 in the low FODMAP diet group Staudacher et al, J Hum Nutr Diet, 2011 Copyright 2015 American College of Gastroenterology 9

10 Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet Patients With Improved Symptom Response, % * * Standard Diet Low FODMAP Diet *P P<0.05 Staudacher HM, et al. J Hum Nutr Diet. 2011;24: IBS & Low FODMAP diet 30 IBS Pts (Rome III) & 8 healthy controls 21 day low FODMAP diet vs. typical Australian diet; cross-over design after 21 day washout Symptoms; stool frequency, and water content Low FODMAP diet led to lower global GI symptom scores (22.8 vs. 44.9; p <.001) Symptoms of bloating, gas and abdominal pain were all improved (all p <.001) Halmos et al Gastroenterology 2014; 46: Copyright 2015 American College of Gastroenterology 10

11 IBS & Low FODMAP Diet: Some Problems Exist What is the cut-off for FODMAP content? Resources differ on low FODMAP diets Total meal FODMAPs should be counted, not individual FODMAP Most patients can t stick to the diet Often requires significant time counseling Theoretical nutritional issues with long-term use IBS-C Copyright 2015 American College of Gastroenterology 11

12 Osmotic Agents: PEG for IBS-C Prospective, multi-center, R, DB, PC Rome III criteria i 139 patients (mean age = 41; 83% women) 28 day study; 13.8 gm/ sachet; 1-3 sachets/day vs. placebo Primary endpoint: mean # of SBM/day Results: At week 4, 4.4 SBM/week vs. 3.1 SBM/week (PEG vs. placebo; p <.0001) PEG 3350+E Improves SBMs in IBS-C * Mean at Week Placebo (n=71) PEG 3350+E (n=68) 0 # SBMs Pain Level SBMs = spontaneous bowel movements; PEG = polyethylene glycol PEG 3350+E is not approved for use in the US Chapman RW, et al. Am J Gastroenterol. 2013;108(9): *P < Copyright 2015 American College of Gastroenterology 12

13 Efficacy of Linaclotide in IBS-C Patients 3 Treatment Period * RW Period z Mean Change From Baseline +/- SEM N=800 BL Weeks Weeks Treatment Period Placebo Linaclotide 290 µg ANCOVA, analysis of covariance; RW, randomized withdrawal. Rao S, et al. Am J Gastroenterol. 2012;107: RW Treatment Sequence Placebo/linaclotide 290 µg Linaclotide 290 µg/linaclotide 290 µg Linaclotide 290 µg/placebo *P< for linaclotide patients vs placebo patients (ANCOVA). P<0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA). Efficacy of Linaclotide for IBS-C Over 12 Weeks % Responders FDA Primary Endpoint ( 6/12 Weeks) 13.9% 33.7%* FDA Primary Endpoint: 30% reduction worst abdominal pain and increase 1 CSBM, both for 6/12 weeks 0 Placebo (n=403) Linaclotide 290 μg (n=401) *P< for all analyses of linaclotide vs placebo groups, using Cochran-Mantel-Haenszel test Chey WD, et al. Am J Gastroenterol. 2012; epub September 18. Copyright 2015 American College of Gastroenterology 13

14 Linaclotide Phase 3 IBS-C Trial: Abdominal Pain Over 26 Weeks % Change in Worst Abdominal Pain Linaclotide 290 µg Placebo -60 BL Trial Week ITT population, observed cases, LS-means presented: P-values based on ANCOVA at each week. Bars represent 95% CI. Diarrhea is the most common adverse event associated with linaclotide treatment; other AEs were comparable between placebo and linaclotide treatment groups. Chey WD, et al. Am J Gastroenterol. 2012; epub September 18. N=804 P= for Week 1 P< for Weeks 2-26 IBS-D Copyright 2015 American College of Gastroenterology 14

15 Rifaximin: Most Extensively Studied Antibiotic for IBS Gut-directed t d antibiotic Not systemically absorbed Doses studied for IBS: 400 mg BID to 550 mg TID Generally well tolerated Adverse effects include: headache, h abdominal pain, and upper respiratory tract infection Ford AC, et al. Clin Gastroenterol Hepatol. 2009;7: Pimentel M, et al. N Engl J Med. 2011;364: Rifaximin Trials: Global Relief of IBS Without Constipation 2 Phase 3 randomized 45 controlled trials; N= patients 35 Rifaximin 550 mg TID x 30 2 weeks; patients followed 25 additional 10 weeks % vs. 31.7% with 15 adequate relief of global 10 symptoms (P<0.001) T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials. 5 0 T-I T-II Comb Rifaximin Placebo Pimentel M, et al. N Engl J Med. 2011;364: Copyright 2015 American College of Gastroenterology 15

16 Screening/ Treatment 1 Phase Study Day 1 Retreatment with Rifaximin Study Design - Target 3 Treatment 2 Phase Maintenance Phase 1 Treatment 3 Maintenance Phase/DBR Phase 2 Treatment Phase Primary Evaluation Period Treatment 4 Phase/SRT Treatment Phase Follow up 7-13 d PBO 2w RFX 4w f/u Up to 18w 2w RFX 4w f/u 6w 2w RFX 4w f/u 1:1 4w EOS Responders with recurrent symptoms Non- Responders Withdrawn 2w PBO 4w f/u 6w 2w PBO 4w f/u Screening/ Treatment 1 Phase Study Day 1 Retreatment with Rifaximin Study Design - Target 3 Treatment 2 Phase Maintenance Phase 1 Treatment 3 Maintenance Phase/DBR Phase 2 Treatment Phase Primary Evaluation Period Treatment 4 Phase/SRT Treatment Phase Follow up 7-13 d PBO 2w RFX 4w f/u Up to 18w 2w RFX 4w f/u 6w 2w RFX 4w f/u * * Non- Responders Withdrawn Responders with recurrent symptoms 1:1 2w PBO 4w f/u Obtain Daily/Weekly Symptom Diary 6w 2w PBO 4w f/u 4w EOS * * * Stool sample collection * Copyright 2015 American College of Gastroenterology 16

17 Target 3: Patient Flow n = 2579 Open Label Discontinued Early n = 248 Non-Responder n = 1257 No Relapse n = 382 (35.6%) Responder at End of Treatment 2 Phase n = 1074 (41.6%) Experienced Relapse (eligible for rand) n = 692 Double-blind Randomized Patients Age: 46.8 Sex: 69% female Placebo n = 308 Discontinued Early n = 37 Rfx 550mg TID n = 328 Discontinued Early n = 44 ReTreatment with Rifaximin in IBS-D IBS-related Abdominal Pain and Stool Consistency (Worst Case Analysis) First and Second Repeat Treatment Phases Rifaximin Placebo = 7.6 = 8.1 of Responders = 9.0 Percentage Responder: Patient responding to IBS-related Abdominal Pain (>30% improvement) and Stool consistency (>50% decrease in # BMs with type 6 or 7) from baseline for 2 of the 4 weeks Copyright 2015 American College of Gastroenterology 17

18 Eluxadoline (Viberzi) for IBS-D: Rationale Mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist Low systemic absorption and bioavailability Low potential for drug drug interactions Animal studies suggest eluxadoline should improve the diarrheal symptoms of IBS-D with limited constipation and durable analgesia μ opioid receptor Activation reduces pain, gastric propulsion δ opioid receptor Inhibition restores G-protein signaling; reduces μ agonist-related desensitization Key inclusion and exclusion criteria Key inclusion criteria IBS-D as defined by Rome III 1-week baseline BSS 5.5 (scale 1 7) WAP >3.0 (scale 0 10) GSS 2.0 (scale 0 4 a ) Additional requirements: Diary compliance No rescue medications during baseline Key exclusion criteria Prior pancreatitis, alcohol abuse, cholecystitis past 6 months, sphincter of Oddi dysfunction, IBD, intestinal obstruction, GI infection or diverticulitis past 3 months Lipase >2x ULN; ALT or AST >3x ULN a 0=no symptoms, 4=very severe symptoms ALT, alanine transaminase; AST, aspartate aminotransferase; BSS, Bristol stool score; GI, gastrointestinal; GSS, global symptom score: IBD, inflammatory bowel disease; ULN, upper limit of normal; WAP, worst abdominal pain in past 24 h Copyright 2015 American College of Gastroenterology 18

19 Phase 3 study design IBS-3001 Prescreen Screening Double-blind treatment Double-blind safety Post-Tx ( 1 wk) (2 3 wks) (26 wks) continuation (26 wks) (2 wks) Randomization (Day 1) Efficacy 12 wks (FDA) Efficacy 26 wks (EMA) End of treatment IBS-3002 Prescreen ( 1 wk) Screening (2 3 wks) Double-blind treatment (26 wks) Blinded PBO withdrawal (4 wks) Randomization (Day 1) Efficacy 12 wks (FDA) Efficacy 26 wks (EMA) Tx, therapy Definition of primary endpoint: composite responder FDA guidance / EMA draft guidance Responder must meet both criteria on same day: Daily pain responder: AND Daily stool consistency responder: WAP scores improved by 30% compared to average baseline pain BSS score <5 (or in absence of BM, if accompanied by 30% improvement in WAP compared to average baseline pain) Above met on at least 50% of days in Weeks 1 12 (FDA), Weeks 1 26 (EMA) Minimum 60 days (FDA) / 110 days (EMA) diary compliance Bonferroni adjustment: to preserve the family-wise error rate for each active group vs placebo (p<0.025) BM, bowel movement Copyright 2015 American College of Gastroenterology 19

20 Phase 3 baseline characteristics Screened, n Randomized, n Age, mean (SD) 44.9 (13.7) 45.9 (13.5) Female, n (%) 838 (65.4) 768 (67.0) >65 years, n (%) 115 (9.0) 126 (11.0) Cholecystectomy, n (%) 272 (21.2) 224 (19.5) Loperamide use, n (%) a 466 (36.3) 408 (35.6) BSS, mean (SD) 63(04) 6.3 (0.4) 62(04) 6.2 (0.4) WAP, mean (SD) 6.2 (1.5) 6.0 (1.5) No. BMs/day, mean (SD) 4.9 (2.8) 4.8 (3.0) GSS, mean (SD) 2.9 (0.5) 2.8 (0.5) a In previous year SD, standard deviation Primary endpoint: composite responders pooled data * 9.5* 7.2* 11.5* 25 Responders (%) N=808 N=806 N=809 N=808 N=806 N=809 Weeks 1 12 Weeks 1 26 *p<0.001 Copyright 2015 American College of Gastroenterology 20

21 Common Adverse Events (> 2% and > PBO; Phase 3) System Organ Class Preferred Term Elux 75 mg BID (N=807) n(%) Elux 100 mg BID (N=859) n (%) Placebo BID (N=808) n (%) Total number of adverse events Number of subjects with at least one adverse event 486 (60.2) 500 (58.2) 450 (55.7) Gastrointestinal disorders 242 (30.0) 228 (27.7) 157 (19.4) Nausea 65 ( 8.1) 64 ( 7.5) 51 ( 5.1) Constipation 60 ( 7.4) 74 ( 8.6) 20 ( 2.5) Abdominal pain 33 ( 4.1) 43 ( 5.0) 22 ( 2.7) Vomiting 32 ( 4.0) 36 ( 4.2) 11 ( 1.4) Flatulence 21 ( 2.6) 27 ( 3.1) 13 ( 1.6) Abdominal distension 21 ( 2.6) 22 ( 2.6) 13 ( 1.6) Infections and infestations 199 (24.7) 190 (22.1) 197 (24.4) Upper respiratory tract infection 27 ( 3.2) 47 ( 5.5) 32 ( 4.0) Nasopharyngitis 33 ( 4.1) 23 ( 2.7) 27 ( 3.3) Sinusitis 27 ( 3.2) 47 ( 5.5) 32 ( 4.0) Bronchitis 26 (32) 3.2) 27 (31) 3.1) 18 (22) 2.2) Urinary tract infection 17 ( 2.1) 15 ( 1.7) 15 ( 1.9) Gastroenteritis viral 22 ( 2.7) 9 ( 1.0) 15 ( 1.9) Nervous system disorders 81 (10.0) 99 (11.5) 88 (10.9) Dizziness 21 ( 2.6) 28 ( 3.3) 17 ( 2.1) Investigations 77 ( 9.5) 68 ( 7.9) 73 ( 9.0) Alanine aminotransferase increased 17 ( 2.1) 26 ( 3.0) 12 ( 1.5) Psychiatric disorders 34 ( 4.2) 46 ( 5.4) 39 ( 4.8) Anxiety 10 ( 1.2) 19 ( 2.2) 14 ( 1.7) Vascular disorders 25 ( 3.1) 22 ( 2.6) 22 ( 2.7) Hypertension 20 ( 2.5) 12 ( 1.4) 14 ( 1.7) Summary The field of IBS is constantly evolving Rome IV 2016 expect changes in the definition Our understanding of IBS physiology continues to expand New treatment options have just been approved Expect other new agents within the next few years Copyright 2015 American College of Gastroenterology 21

22 Copyright 2015 American College of Gastroenterology 22