Quick viewing(Text Mode)

Are There Any New Therapies for Constipation and IBS?

Are There Any New Therapies for Constipation and IBS?

Are there Any New Therapies for and IBS?

Chris Andrews, University of Calgary Louis Liu, University of Toronto

February 10, 2014

Accreditation

This event has been approved as an accredited (Section1) group learning activity as defined by the Maintenance of Certification program of the RCPSC. It has been produced under RCPSC guidelines for the development of co-developed educational activities between CAG and Forest Laboratories Canada Inc.

Name: Dr. Christopher N. Andrews

Financial Disclosures (over past 24 months)

Speaker Advisory Research Consultant

Janssen √ √ √ √ Pharmaceuticals Takeda Canada Inc √ Pendopharm √ AbbVie √ Forest √ Pharmaceuticals

Name: Dr. Louis Liu

Financial Disclosures (over past 24 months)

Speaker Advisory Research Consultant Janssen √ √ √ Pharmaceuticals Takeda Canada Inc √ √ Abbott Canada √ √ Pendopharm √ AbbVie √ Ferring √ Pharmaceuticals Aptalis √ Forest √ Pharmaceuticals Learning Objectives

At the end of this session, participants will be able to:

• Translate the definitions of constipation and IBS into practical clinical paradigm • Apply the evidence of the latest clinical trials in the management of constipation and IBS • Integrate these new medical therapies (on the market or soon to come) with existing treatments for constipation and IBS in their practice 2014 CDDW/CASL Winter Meeting

CanMEDS Roles Covered:

Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, √ applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.)

Collaborator (as Collaborators, physicians effectively work within a healthcare team to √ achieve optimal patient care.)

Manager (as Managers, physicians are integral participants in healthcare organizations, √ organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and √ influence to advance the health and well-being of individual patients, communities, and populations.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.)

Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.) Case

• 42 yr old female executive • Experienced constipation since teenager, worsening since 1 year ago o Urge infrequent, 1 BM every 5-6 days o Abdominal discomfort & distension relieved by BM o Fibre worsening , PEG worsening and increase distension, causes severe abdominal cramp • PMH: appendectomy, depression (on ) • Divorced, 2 children (age 12 and 14) • Don’t smoke, EtOH socially • O/E: weight 60 kg, ht 168 cm, thyroid, cardiopulmonary and abdominal examination were normal. DRE – no stool, normal sphincter tone and no detectable paradoxical anal sphincter contraction with straining Rome III Criteria: IBS

1. Recurrent or discomfort at least 3 days/ month in the last 3 months, associated with 2 or more of the following: o Improvement with o Onset associated with a change in frequency of stool o Onset associated with a change in form (appearance) of stool

2. Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

Longstreth GF. Gastroenterology 2006; 130: 1480-91 http://www.romecriteria.org/criteria/ ROME III Criteria: Constipation

1. Must include >2 of the following (past 3 months with at least 6 months from symptom onset): o Straining during at least 25% of o Lumpy or hard stools in at least 25% of defecations o Sensation of incomplete evacuation in at least 25% of defecations o Sensation of anorectal obstruction/blockage for at least 25% of defecations o Manual maneuvers to facilitate at least 25% of defecations o Fewer than 3 defecations per week 2. Loose stool rarely present without the use of

3. Insufficient criteria for irritable bowel syndrome

Longstreth GF. Gastroenterology 2006; 130: 1480-91 http://www.romecriteria.org/criteria/ Chronic constipation and IBS-C

- Abdominal Discomfort / Pain +

CC IBS-C

• Symptom-based criteria for CC and IBS-C may overlap • IBS-C defined by the presence of clinically-important abdominal discomfort associated with constipation

Thompson WG et al, Gut 1999; 45: SII43 Alarm features (Red flags)

• Recent onset of symptoms in patients > 50 years • Rectal bleeding • Significant weight loss • Iron-deficiency with or without anemia (worsening, new onset) • Abnormal physical examination e.g. palpable mass (rectal or abdominal) Lifestyle and algorithm for patients with

Expert assessment If NO response

Prokinec Rescue therapies for occasional Ineffective or intolerant (prucalopride) uses 1. Glycerine suppository 2. Stimulant laxatives, in oral or Osmoc laxave suppository form 3. (e.g. MoM, , PEG)

Fibre supplement

Set appropriate patients’ Eliminated removable factors goals and expectations Counsel on diet and physical acvity

Educaon: Acknowledge and address paent’s concerns Set realisc expectaons & encourage paent parcipaon

Liu, LWC Can J Gastroenterol 2011; Vol 25(B): 26B Adapted by Dr. Liu, Feb/2013 Colonic Motility 5-HT4

Ach = acetylcholine; SP = substance P; NO = nitric oxide; VIP = vasoactive intestinal peptide

Adapted from Prins et al, Br. J Pharmacol 2000;131:927 Three pivotal trials with identical study design

PAC-SYM, patient’s assessment of constipation – symptoms; PAC-QOL, patient’s assessment of constipation - quality of life; 1 Camilleri M, et al. N Engl J Med 2008;358:2344 AE, adverse events; ECG, electrocardiogram 2 Tack JF, et al. Gut 2009;58:357 3 Quigley EM, et al. Aliment Pharmacol Ther 2009;29:3151 Three pivotal trials: Main inclusion criteria • Adult patients (≥ 18 years) or either gender

• History of chronic constipation, defined as: o ≤ 2 SCBM/week for a minimum of 6 months o ≥ 1 of the following symptoms for at least 25% of stools: o Very hard (little balls) and/or hard stools o A sensation of incomplete evacuation o Straining during defecation • Identical inclusion criteria and endpoints so the study results could be pooled

SCBM: Spontaneous Complete Bowel Movement 1 Camilleri M, et al. N Engl J Med 2008;358:2344 2 Tack JF, et al. Gut 2009;58:357 3 Quigley EM, et al. Aliment Pharmacol Ther 2009;29:3151 Three pivotal trials: Endpoints1–3

Primary efficacy • Proportion of patients with a mean of ≥ 3 SCBM/week, over a 12-week treatment endpoint period (*normalization of BM)

• Proportion of patients with an increase of ≥ 1 SCBM/week • Bowel movements, stool consistency and Secondary efficacy straining endpoints • Endpoints derived from validated disease- specific questionnaires: ⎯ PAC-SYM4 ⎯ PAC-QOL5

PAC-SYM: Patient’s assessment of constipation – symptoms PAC-QOL: Patient’s assessment of constipation – quality of life SCBM: Spontaneous Complete Bowel Movement 1 Camilleri M, et al. N Engl J Med 2008;358:2344 2 Tack JF, et al. Gut 2009;58:357 3 Quigley EM, et al. Aliment Pharmacol Ther 2009;29:315 4 Frank L, et al. Scand J Gastroenterol 1999;34(9):870 5 Marquis P, et al. Scand J Gastroenterol 2005;40(5):540 Prucalopride for Chronic Constipation: A Meta-Analysis of the Large RCTs

Gatta, Kerstens & Scarpignato, Gastroenterology 2013; 144 (Suppl 1): S457 Significant PAC-QOL Improvements

• “In these studies an improvement of 0.5 point was considered clinically meaningful”5

1 Tack JF. Poster, XXIst Belgian Week of Gastroenterology 2009 2 Tack JF, et al. Gut 2009;58:357 PAC-QOL: Patient’s assessment of constipation – 3 Quigley EM, et al. Aliment Pharmacol Ther 2009;29:315 quality of life which incorporates 4 subscales measuring physical discomfort, psychosocial 4 Camilleri M, et al. N Engl J Med 2008;358:2344 discomfort, worries and concerns and satisfaction. 5 Marquis P et al. Scan J of Gastro 2005: 40:540-551 Favorable safety and tolerability profile • Most frequent drug-related adverse events* (%), pooled data from three pivotal phase III studies (12-weeks treatment period)

* Defined as adverse events occurring in ≥5% patients in any prucalopride treatment group

1 Tack JF et al. DDW 2008; T1322 Mechanism of action of

Parker C, Yuan C and Liu LWC. Clin Med Insights: Gastroent 2013:6; 21-32. Linaclotide in CC

n = 642

Primary end point: ≥ 3 CSBMs/wk & an increase of ≥ 1 CSBM/wk from baseline for 9 or more weeks during the 12-week treatment period n = 1276, Lembo AJ et al. NEJM. 2011; 365(6): 527-36. Chronic constipation and IBS-C

- Abdominal Discomfort / Pain +

CC IBS-C

• Symptom-based criteria for CC and IBS-C may overlap • IBS-C defined by the presence of clinically-important abdominal discomfort associated with constipation

Thompson WG et al, Gut 1999; 45: SII43 Source: Gastroenterology (DOI:10.1053/j.gastro.2013.08.017 ) Dietary Modification in IBS • FODMAP : "Fermentable, Oligo-, Di-, Mono-saccharides And Polyols" • Short chain carbohydrates that are poorly absorbed in the small intestine

Gibson and Shepard. J Gastro Hep 2010; 25 (2): 252–258. Low FODMAPS Diet in IBS

• 30 IBS pts and 8 HC • 21 days of typical Australian diet or low FODMAPS • Crossover with 21d washout /blinded

Halmos et al. Gastroenterology (2013), doi: 10.1053/j.gastro.2013.09.046. Gluten Free Diet in Non-Celiac IBS

• 44 patients with IBS-D randomized to gluten free diet (GFD) or gluten-containing diet (GCD) for 4 weeks

• Less BM, less SB permeability on GFD

Vazquez-Roque et al. Gastro 2013 May;144(5):903-911.e3 Probiotics • What is the evidence? o VSL #3 • Bloating only symptom to improve o O’Mahoney, Gastroenterology 2005 • Bifidobacterium infantis 35624 (Align) • Reduction in symptoms • Modest improvement in Quality of Life o Nobaek S Am J Gastro 2000 • Lactobacillus plantarum 299v (TuZen) • Reduction in flatulence and overall GI function (p=0.06) Case

• Constipation initially controlled with medical therapies

• 10 years later, developed chronic back pain o Started on narcotics o Constipation worsen

• Fibromyalgia

• Wondering about whether she needs to go on disability Agents for opioid-induced constipation

• o Peripheral o Does not cross the blood brain barrier o S.c. injection every few days o Only indicated for terminal patients

• Oxycodone with (Targin) o Oral naloxone is poorly absorbed o Works on gut to reverse narcotic effect o Oxycodone sustained release with fixed dose of naloxone (eg 5/2.5, 10/5, etc) o Tamper proof Improves Early Satiation, Nutrient Intake, Weight Recovery and Quality of Life in Functional Dyspepsia (FD) With Weight Loss: a Double-Blind, Randomized, Placebo-Controlled Pilot Study • Mirtazapine, (noradrenergic-) with H1-, α2-, 5-HT2c- and 5-HT3-receptor antagonistic properties (15mg HS x 8 wks) • 34 FD pts (5 male, mean age 36±2) with weight loss (mean 13.2±2.8kg) were enrolled, 4 dropouts, 2 placebo (lack of effect), 2 mirtazapine (somnolence)

Huynh et al. DDW 2013 Linaclotide in IBS-C • 2 phase III multicenter RCT, • The primary endpoints o FDA recommended endpoint: > 30% improvement in abdominal pain & an increase of ≥ 1 CSBM/wk above baseline for at least 6 of 12 wk o > 30% improvement in abdominal pain for at least 9 of 12 wk o ≥ 3 CSBMs/wk with an improvement of ≥ 1 above baseline for at least 9 of 12 wk o a combination of the last 2 endpoints • Secondary end points o improvement in abdominal pain, abdominal discomfort, bloating, stool frequency and consistency, the need to strain, cramping, fullness, severity of IBS symptoms and constipation, the degree and adequacy of relief from IBS symptoms and patient satisfaction o All secondary end points were statistically improved with linaclotide treatment Phase 3 Trials in IBS-C: Primary Endpoints

Trials evaluated Abdominal Pain Responders, CSBM Responders and Combined Responders

Abdominal Combined CSBM Pain Responders Frequency

Combined responders demonstrated significant improvements on TWO measures

Responder Definitions Combined Responder

CSBM >3 AND increase of >1 over baseline At least 9/12 weeks Abdominal pain >30% reduction over baseline P

CSBM Increase of >1 over baseline At least 6/12 weeks Abdominal pain >30% reduction over baseline P

32 Linaclotide in IBS-C

FDA end point

*** p < 0.001 **** p < 0.0001 Linaclotide, n = 405 Placebo, n = 395 Rao, S et al. AJG, 2012; 07:1714–1724 Patient information Websites

• AGA: Patient Center – “IBS: A Patient's Guide to Living with Irritable Bowel Syndrome”

o http://www.gastro.org/patient-center/digestive-conditions/irritable-bowel- syndrome#Living%20with%20IBS

• Canadian Digestive Health Foundation o http://www.cdhf.ca/en/disorders/details/id/12 Evaluation and Certificate of Attendance

Please visit the CAG website at http://www.cag-acg.org/ to complete the session evaluation and to print your certificate of attendance.

Thank you!

Top View