Irritable Bowel Syndrome - swpca.caswpca.ca/Uploads/ContentDocuments/IBS2019.pdf · What is...
Transcript of Irritable Bowel Syndrome - swpca.caswpca.ca/Uploads/ContentDocuments/IBS2019.pdf · What is...
Irritable Bowel SyndromeBenson Thomas FRCPC GastroenterologySt Thomas Elgin General Hospital
Objectives
bullUnderstand the epidemiology etiology and impact of IBS for the patients
bullReview a simple diagnosis and management algorithm
bullUnderstand the evidence to support the clinical utility of the latest Rx products
Introduction to IBS
3
Epidemiology of ldquoCommonrdquo GI Disorders
1 Lovell RM Ford AC Clin Gastroenterol Hepatol 201210(7)712-721 2 Suares NC Ford AC Am J Gastroenterology 2011106(9)1582-1591 3 Tysk C et al Ann Gastroenterol 201124(4)253-262 4 Ye Y et al Int J Clin Exp Med 20158(12)22529-22542 5 Cash BD et al Gastroenterology 2011141(4)1187-1193
Prevalence
4
Chart1
Sheet1
What is Irritable Bowel Syndromebull Functional GI disorder with multiple etiologies ndash no cure
bull Chronic symptoms attributable to middle or lower GI tract
bull Absence of organic cause (eg structural or biochemical)
bull In Canada 5 million suffer from IBS (10 of people in literature)
bull 20-50 of GI referrals 10 GP visits 2 cause of missing work
Longstreth GF et al Gastroenterology 20061301480 Lacy BE et al Gastroenterology 20161501393 Fedorak RN et al Can J Gastroenterol 201226252
Lovell RM Ford AC Clin Gastroenterol Hepatol 2012 10712 5
bull Recurrent abdominal pain associated with two or more of the following
ndash Change in frequency of stoolndash Change in form (appearance)
of stoolndash Related to defecation
bull Pain occurring on average at least 1 day per week in the last 3 months
bull Symptom onset at least 6 months before diagnosis
Rome IV Diagnostic Criteria for IBS
Subtypes of IBS
Lacy BE et al Gastroenterology 2016150(6)1393-1407e5
Type 1
Type 2
Type 3
Type 7
Type 5
Type 6
Type 4
Bloating
Pain
Distension
IBSM
C
D
FC
FDr
Con
stip
atio
n
FC Functional constipationFDr Functional diarrheaIBS-C Irritable bowel syndrome with predominant constipationIBS-D Irritable bowel syndrome with predominant diarrhea IBS-M Irritable bowel syndrome with mixed bowel habits (D and C)
Functional Bowel Disorders are a Spectrum
Lacy BE et al Gastroenterology 2016150(6)1393-1407e5 7
Possible Causes of IBS
Feldman et al Sleisenger and Fordtran s Gastrointestinal and Liver Disease 10th ed 2016 (Adapted)rsquo
IBS
Visceral hyper-
sensitivity
Abnormal gut motility
Brain gut interaction
Post infection inflammationGenetics
Altered Fluid Homeostasis
Altered microbiome
CIC IBS-CLong term (ge6 months)
lt 3 stools per week
Stool form that is mostly hardlumpydagger
Difficult stool passage (straining andor incomplete evacuation)dagger
Abdominal pain
Symptoms ge3 months onset ge6 months prior to diagnosis
Abdominal pain distinguishes CIC amp IBS-C
No known underlying cause daggerge25 of the timeCIC=chronic idiopathic constipation IBS-C=irritable bowel syndrome-constipation Pare P et al Can J Gastroenterol 200721(Suppl B) 3B-22B 2 Irvine EJ et al Am J Gastroenterol 2002 Aug97(8)1986-93 3Pareacute P et al Clin Ther 2006 Oct28(10)1726-35 discussion 1710-1 9
The impact of IBS on patients
Hysterectomy and appendectomy were 2-fold higher and cholecystectomy was 3-fold higher in patients with IBS vs patient who did not have IBS3
1 Furnari M et al Ther Clin Risk Manag 201511691ndash703 2 Spiller R et al Gut 2007561770ndash1798 3 Longstreth GF Yao JF Gastroenterology 20041261665minus1673 4 Canavan C et al Aliment Pharmacol Ther 2014401023ndash1034
Regular visits to HCPs
Reduced work
productivity
Disturbed sleep
Long-term medication useAnxiety
depression
Burden on patientsrsquo quality of life1ndash3 On average patients would
sacrifice 10ndash15 years of remaining life
expectancy for an immediate cure4
Unnecessary surgeries
investigations
Presence of comorbidities
can further reduce quality
of life
Dietary restrictions
IFFGD IBS Patients Their Illness Experience and Unmet Needs 2009IBS in America summary findings AGA data extracted from full raw data set December 2015 11
IBS Patients are Dissatisfied and Frustrated
Extremely satisfied
3
Very satisfied
5
Somewhat satisfied
29
A little bit satisfied
29
Not at all satisfied
34
74
48
3937
34
28
2018
4 41
0
20
40
60
80
Res
pond
ents
( n
= 3
254
)
Diagnosis and Management of IBS
12
Diagnosis and Management of IBS
Identify key patient characteristics
Educate and reassure the patient
Optimise treatment
Follow up
1
2
3
4
Assess
Diagnose
1
2
IBS diagnosis algorithm1
Patient presents with defining symptoms
IBS management algorithm1
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
ROME IV diagnostic criteria
Patient presenting with symptoms suggestive of IBS1
Bristol Stool Form Scale
IBS subtypes
The following tools can aid in establishing a diagnosis of IBS
Recurrent bothersome symptoms for at least 3 months
ABDOMINAL PAIN ALTERED BOWEL HABIT (constipation diarrhoea or both)+
Typically the first point at which patients with
suspected IBS will consult a physician is when their
symptoms are bothersome enough to affect their daily life1
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Reaching a positive diagnosis of IBS1
Recurrent bothersome symptoms for at least 3 months
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
1 bull Conduct a history and physical exambull Investigations should be minimal ndash (can be a challenge)bull If concerns exist for organic disease conduct further investigations
ASSESS
ABDOMINAL PAIN ALTERED BOWEL
HABIT (constipation diarrhoea or both)
+
Patient meets diagnostic criteria
Features that may cause concern for organic pathology1
bull Age 50 years or above bull Blood in stools (unless of anal
origin ndash haemorrhoids or fissures)bull Unintended weight loss bull Unexplained anaemia bull Family history of IBD coeliac
disease or colon cancer
bull Abdominal mass bull Ascites bull Elevated white blood cell count bull Loss of appetitebull Nocturnal symptomsbull Fever bull Recent change in symptoms
These features should be considered in the context of the supportive features marked changes or the presence of multiple features
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Assessment and investigation(historyphysical exam)1
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Identify symptom triggers(eg diet stress)
Assess impact on daily life
Assess for psychological comorbidities
Assess for other physical comorbidities(eg gynaecological urological)
Explore patientrsquos values and preferences
Limited laboratory studies to help distinguish IBS from other gastrointestinal conditions1
Complete blood countIf anaemia or an elevated white
blood cell count is detected further investigation should be conducted
C-reactive protein and faecal calprotectin
To exclude IBD or other inflammatory conditions in individuals with diarrhoea
Further questions to confirm a positive diagnosis of IBS1
Abdominal pain Altered bowel habit(constipation diarrhoea or both)
Defining symptoms
+
Bloating distention flatulence Abdominal symptoms
Non GI symptoms Migraines interstitial cystitis dyspareunia constant lethargy
Pain relievedworsened by bowel movements
Further features supportive of diagnosis
Pattern duration and location important
Consistent with diagnosis but not always present
The nature and onset of symptoms is also important (eg in
relation to episodes of gastroenteritis
stressful events etc)1
Presence of other functional GI disorders may support IBS diagnosis
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Reaching a positive diagnosis of IBS1
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
1 bull Conduct a history and physical exambull Investigations should be minimalbull If concerns exist for organic disease conduct further investigations
ASSESS
Recurrent bothersome symptoms for at least 3 months
ABDOMINAL PAIN ALTERED BOWEL HABIT (constipation diarrhoea or both)+
Patient meets diagnostic criteria
2 bull If there are no concerns for organic pathology give a POSITIVE diagnosis of IBS
DIAGNOSE
IBS management algorithm at a glance1
Identify key patient characteristics
bull Identify the predominant symptom(s)bull Consider previous therapies
preferences and patient expectations
Educate and reassure the patient
bull NAME and EXPLAIN the conditionbull Provide reassurance
1
2
Optimize treatment bull Consider non-pharmacological and
pharmacological treatments based on the predominant symptom patient preferences and expectations
Follow upbull Reassess at 4ndash8 weeksbull Assess relief satisfaction
compliance and tolerability strategies
3
41 Moayyedi P et al United European Gastroenterol J 20175773ndash788
When deciding on an appropriate treatment strategy it is important to understand the clinical profile of the patient
Identify key patient characteristics1
Predominant symptom
Impact on quality of
life
Treatment history
Patient preferences
Patient goals
Including pattern and
severity
Symptom impact on
daily activities
Over the counter and prescription
medications
Eg for non-pharmacologic
altherapies
Expectations for therapy
Psychological comorbidities
May contribute to worsening of symptoms
1
Adapted from Moayyedi P et al 20171
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Educate and reassure the patient12
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
Providing patients with a written diagnosis of IBS rather than just verbal confirmation
NAME and EXPLAIN IBS to patients using patient-friendly terminology
Build a strong patient-physician relationship Using active listening not interrupting empathy setting realistic patient expectations eye contact and open body posture
Use simple visual tools to simplify the complex pathophysiology of IBS
Teach patients simple self-management strategies Related to diet and stress management
Reassure the patients to reduce their symptom-related fears and anxiety
Establishing a strong patient-physician relationship at this early stage ndash getting to the
root of the patientrsquos concerns and explaining their
condition ndash is a crucial step towards finding an effective
management strategy1
Evidence Based Recommendations on IBS Management
23
3
Optimize treatment1Start with conservative management3
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
3 Conservative management
Lifestyle and dietary modifications (usually tried BEFORE pharmacological interventions and advanced management strategies)
Regardless of subtype or predominant
symptoms for many patients the first-line
approach of lifestyle and dietary modifications
may provide relief from IBS without the need for
further interventions1
Modifying dietary fibre
Promoting increased physical activity
Encouraging healthy eating habits
Modifying the intake of alcohol caffeine fat spicy food and gas-producing foods
Restricting milk and dairy products
Investigating potential carbohydrate
malabsorption
Adapted from Moayyedi P et al 20171
Dietbull Fiber (RCT evidence) in IBS-C
- May benefit constipation and provide some global symptom benefit
- Not helpful for pain or diarrheabull Consider trial of Lactose and gluten
avoidancebull Reduce excess fructose fatty foods gas-
producing foods caffeine alcoholbull Specific diets FODMAPs
FODMAPs
bullFermentable Oligo- Di- and Mono-saccharides And Polyols
bullShort chain carbohydrates that are poorly absorbed As a resultndash Osmotically activendash Rapidly fermented
27
ProbioticsbullMixed results low quality studiesbullProbably most potential for benefit in IBS-D
Antispasmodicsbull 2011 Meta-analysis antispasmodics superior to
placebobull Smooth Muscle Relaxants
ndash Pinaverium (Dicetel)ndash Trimebutine (Modulon)
bull Anticholinergicndash Dicyclominendash Buscopan
Antidepressantsbull TCAs (amitriptyline desipramine)
ndash Meta-analyses have included low-quality studies report NNT 3-4 for improvement in global well-being
ndash Large RCT - Desipramine vs placebo ndash in female patients 60 vs 47 response
ndash May be most beneficial in diarrhea-predominant IBSndash Up to 40 discontinue use because of intolerance
bull SSRIs SNRIsndash Fewer side effects RCTs report more mixed results
Herbal MedicinesPeppermint oil = active ingredient is mentholndash Has antispasmodic propertiesndash Ibgard ndash slow release formulation has some RCT
data to support its usendash Meta-analysis of 5 RCTs showed significant global
improvement of IBS-Sx compared with placebo
Antibioticsbull Two Phase 3 RCTs (1260 pts) for non-constipation IBS
rifaximin 550mg tid x 14d improved global Sx and individual Sx (bloating AP stool consistency) vs placebo
ndash Benefits persisted up to 3 months ndash alteration of flora
ndash Side effects Safe ndash no C diffndash Long term prognosis (gt10 weeks) unknown
3
Optimize treatment1Target therapy towards predominant symptoms3
1 Moayyedi P et al United European Gastroenterol J 20175773ndash788
3 Conservative management
Lifestyle and dietary modifications (usually tried BEFORE pharmacological interventions and advanced management strategies)
If patients do not respond or are refractory to these measures base the sequence of treatments on
Predominant symptoms
Quality of evidence
Individual patient
assessment
Preference and availability
Management targeted at predominant symptom (order of use according to IBS subtype)
IBS-D IBS-MIBS-CDiarrhea
Bloating
Pain
Constipation
Bloating
Pain
Laxative user
Loperamide user
Pain
Figure adapted from Moayyedi P et al 20171
IBS-D
Diarrhea Bloating Pain bull Loperamidebull Eluxadolinebull Cholestyramine bull Ondansetron bull Rifaximin
bull Rifaximin bull Eluxadolinebull Low-FODMAP dietbull Probiotics
bull Antispasmodicsbull Eluxadoline bull TCAs bull Psychological therapybull Bile acid sequestrantsbull Probiotics
IBS-C
Constipation Bloating Pain bull Water soluble fibrebull Laxativesbull Linaclotidebull Lubiprostonebull Prokinetics
bull Linaclotide bull Lubiprostonebull Low-FODMAP dietbull Probiotics
bull Linaclotide bull Antispasmodicsbull SSRIsbull Psychological therapybull Probiotics
IBS-M
Laxative user Loperamide user Pain bull Stop laxative bull Stop loperamide
bull Low-FODMAP dietbull Antispasmodicsbull SSRIs or TCAsbull Psychological therapybull Probiotics
Predominant symptoms Quality of evidence Individual
patient assessment Preference
and availability
If patients do not respond or are refractory to lifestyledietary modifications base the sequence of treatments on
Optimize treatment1IBS management options at a glance 3
Figure adapted from Moayyedi P et al 20171
Some classes of drug referred to may not be licensed for use in IBS Refer to the relevant Product Monograph of each product for their approved indication Eluxadoline is indicated in adults for the treatment of IBS-D6 Linaclotide is indicated for the treatment of IBS-C and CIC in adults11
EluxadolineMechanism of Action
Eluxadoline Mechanism of Action
δmicroκ δmicroκ+ ndash+
Eluxadoline binds opioid receptors
in the GI tract
Eluxadoline agonizes κ and micro opioid
receptors
Eluxadoline antagonizes
δ opioid receptorsδ antagonism modulatesmicro agonism
δmicroκ δmicroκ+ ndash+
δ antagonism modulatesmicro agonism
Lumen
Mucosa
Submucosa
Pain fibresPain fibres
Patients with IBS-D experienceEluxadoline
Increased GI transit 1Slows GI transit 1
2Increased secretion 2Decreases secretion
3Visceral pain 3Reduces visceral pain
Dove LS et al Gastroenterology 2013145329 Fujita W et al Biochem Pharmacol 201492448 Wade PR et al Br J Pharmacol 20121671111 Viberzi (eluxadoline)
[prescribing information] Parsippany NJ Actavis Pharma Inc 2016 36
SAFETY CONTINUATION
Pivotal Double-Blind Phase 3 Trials
BID twice a day EMA European Medicines Agency FDA US Food and Drug Administration PBO placebo withdrawal period PTX post treatmentLembo AJ et al N Engl J Med 2016374242 37
END OF TREATMENT52 weeks
EFFICACY
IBS-3001
EFFICACY12 weeks (FDA)
EFFICACY26 weeks (EMA)
PTX(2 weeks)BIDPlacebo (n=427)
PTX(2 weeks)75 mg BIDEluxadoline (n=427)
PTX(2 weeks)100 mg BIDEluxadoline (n=426)
SCREENING(2ndash3 weeks)
PRE-SCREEN(le1 week)
0 5212 26 39
PBO(4 weeks)
PBO(4 weeks)
PBO(4 weeks)
IBS-3002Placebo (n=382) BID
Eluxadoline (n=381) 75 mg BID
Eluxadoline (n=382) 100 mg BID
SCREENING(2ndash3 weeks)
PRE-SCREEN(le1 week)
Time (weeks)
RANDOMIZATION111 (day 1)
400
457495
437
528 537
0
25
50
75
n=427 n=427 n=426 n=382 n=381 n=383
plt005 vs placebo Cochran-Mantel-Haenszel analysis of the intention-to-treat populationAdequate Relief Responders were patients who reported adequate relief for ge50 of weeks based on
response to the following question asked each week (1-26) ldquoHave you had adequate relief of your IBS symptomsrdquo Lembo AJ et al N Engl J Med 2016374242 TRUBERZI (eluxadoline) [summary of product characteristics] Aptalis Pharma SAS 2016Courbevoie France
SECONDARY ENDPOINT
Adequate Relief
438
529 542
492
601584
0
25
50
75
n=427 n=427 n=426 n=382 n=381 n=382
38
Res
pond
ers
()
IBS-3001 IBS-3002 IBS-3001 IBS-3002
Placebo Eluxadoline 75 mg Eluxadoline 100 mg
Weeks 1ndash12 Weeks 1ndash26
Res
pond
ers
()
341
446 455
166
266 279
0
25
50
75
plt00001 vs placebo An urgency-free day was any day on which a patient recorded a ldquozerordquo for the number of urgency episodes (sudden almost irresistible need to have a bowel movement) in the past 24 hours regardless of the number of bowel movements
Lembo A et al Presented at ACG 2014 Philadelphia PA
SECONDARY ENDPOINT
Urgency-Free Days Post Hoc Analysis
293
406 407
143
238 232
0
25
50
75
39
Res
pond
ers
()
50 urgency-free days
75 urgency-free days
50 urgency-free days
75 urgency-free days
Weeks 1ndash12 Weeks 1ndash26
R
espo
nder
s (
)
Placebo Eluxadoline 75 mg Eluxadoline 100 mg
Pooled IBS-3001 and IBS-3002 data
At baseline patients reported a mean of 35 urgency episodesday and 10ndash14 incontinence episodesday
EluxadolineSafety and Tolerability
40
Anatomy of the Bile Duct
41
Sphincter of Oddi Spasm and Pancreatitis Events in Clinical Trials
Of whom 165 did not have a gallbladder daggerOf whom 184 did not have a gallbladder DaggerOccurred only in patients without a gallbladderULN upper limit of normal
Viberzi (eluxadoline) [prescribing information] Parsippany NJ Actavis Pharma Inc 2016 42
Eluxadoline 75 mg(n=807)
Eluxadoline 100 mg(n=1032)dagger
Sphincter of Oddispasm (SOS)Dagger
All events resolved upon treatment discontinuation typically improving by the
following day 80 of cases occurred within
1 week of treatment and the rest within 1 month
2 (02) 8 (08)
bull 1 patient had abdominal pain and elevated hepatic enzymes
bull 1 patient had abdominal painand lipase elevation lt3x ULN
bull 7 patients had abdominal pain and elevated hepatic enzymes
bull 1 patient had pancreatitis occurring within minutes of taking treatment
Pancreatitis
All pancreatic events resolved with lipase normal-
ization upon treatment discontinuation 80 of
cases resolved within 1 week
2 (02) 3 (03)
bull 3 patients had excessive alcohol intake
bull 1 patient had biliary sludge
bull 1 patient discontinued treatment prior to symptom onset
Adverse reaction () Placebo(n=975)
Eluxadoline 75 mg(n=807)
Eluxadoline 100 mg(n=1032)
Constipation 2 7 8
Nausea 5 8 7
Abdominal pain 4 6 7
Upper respiratory tract infection 4 3 5
Vomiting 1 4 4
Nasopharyngitis 3 4 3
Abdominal distension 2 3 3
Bronchitis 2 3 3
Dizziness 2 3 3
Flatulence 2 3 3
Rashdagger 2 3 3
Increased ALT 1 2 3
Fatigue 2 3 2
Viral gastroenteritis 2 3 1
Common Adverse Reactions
The table shows ADE reported in phase 2 and 3 studies in gt2 of eluxadoline-treated patients at either dose and at an incidence greater than in placebo-treated patients During the 4-week single-blind withdrawal period in Study 2 no evidence of worsening of diarrhea or abdominal pain compared to baseline was
demonstrated at either dose Includes abdominal pain abdominal pain lower and abdominal pain upper daggerIncludes dermatitis dermatitis allergic rash rash erythematous rash generalized rash maculopapular rash papular rash pruritic urticaria and idiopathic urticaria
Viberzi (eluxadoline) [prescribing information] Parsippany NJ Actavis Pharma Inc 2016 43
Adverse reaction () Placebo(n=975)
Eluxadoline 75 mg(n=807)
Eluxadoline 100 mg(n=1032)
Constipation 2 7 8
Nausea 7 8 5
Abdominal pain 7 6 4
Upper respiratory tract infection 5 3 4
Vomiting 4 4 1
Nasopharyngitits 3 4 3
Abdominal distension 3 3 2
Bronchitis 3 3 2
Dizziness 3 3 2
Flatulence 3 3 2
Rashdagger 3 3 2
Increased ALT 3 2 1
Fatigue 2 3 2
Viral gastroenteritis 1 3 2
Common Adverse Reactions
The table shows ADE reported in phase 2 and 3 studies in gt2 of eluxadoline-treated patients at either dose and at an incidence greater than in placebo-treated patients During the 4 week single-blind withdrawal period in Study 2 no evidence of worsening of diarrhea or abdominal pain compared to baseline was
demonstrated at either dose Includes abdominal pain abdominal pain lower and abdominal pain upper daggerIncludes dermatitis dermatitis allergic rash rash erythematous rash generalized rash maculopapular rash papular rash pruritic urticaria and idiopathic urticaria
Lembo AJ et al N Engl J Med 2016374242 Viberzi (eluxadoline) [prescribing information] Parsippany NJ Actavis Pharma Inc 2016 44
Eluxadoline should be discontinued in patients who develop severe constipation for more than 4 days
bull Most constipation events occurred within the first 3 monthsof therapy with ~50 occurring within the first 2 weeks
bull Rates of constipation were similar between active and placebo arms beyond 3 months of treatment
bull Severe constipation occurred in lt1 of eluxadoline patients
bull No serious complications from constipation were reported
Linaclotide Mechanism of Action
Alignment with Functional GI Disease Pathophysiology
45
Linaclotide Mechanism of Action
1 Vaandrager AB Mol Cell Biochem 2002 230(1-2)73-83 2 Eutamene H et al Neurogastroenterol Motil 2010 22 312ndashe843 Castro J et al Gastroenterol 2013 145(6)1334-46
Lumen Serosa
GC-C = guanylate cyclase-C GTP = guanosine triphosphate cGMP = cyclic guanosine monophosphate NHE-3 = sodium-hydrogen exchanger 3 PKGII = protein kinase G type II CFTR = cystic fibrosis transmembrane conductance regulator
Based on findings from animal studies clinical relevance in humans has not been established
46
Canadian Constellareg (linaclotide) indications
Constellareg (linaclotide) Product Monograph Forest Laboratories Canada Inc May 12 2014
Irritable Bowel Syndrome with Constipation (IBS-C)Constellareg (linaclotide) is indicated for the treatment of irritable bowel syndrome with constipation in adults
Chronic Idiopathic Constipation (CIC)Constellareg (linaclotide) is indicated for the treatment of chronic idiopathic constipation in adults
47
Constellareg in IBS-C
Chey WD et al Am J Gastroenterol 2012 Nov107(11)1702-12Rao S et al Am J Gastroenterol 2012 107(11)1714-24 48
Phase 3 Trials in IBS-C Baseline Characteristics
Trial 302 Trial 31Placebo(N=403)
Linaclotide290 ug (N=401)
Placebo(N=395)
Linaclotide290 ug (N=405)
Mean age 44 446 437 433
Age ge65 () 17 (42) 23 (57) 26 (66) 19 (47)
Female () 352 (873) 368 (918) 357 (904) 367 (906)
White () 311 (772) 316 (788) 301 (762) 314 (775)
BMI 277 278 276 283
CSBMsweek 02 02 02 02
SBMsweek 17 17 19 19
Stool consistency (BSFS) 23 24 24 23
Straining score 35 36 34 36
Constipation severity score 38 38 37 38
IBS symptom severity 37 37 37 37
Mean CSBM frequency was 02 CSBMsweek76 of patients had 0 CSBMs during
2 week pretreatment period
CSBMsweek
Rao S et al Am J Gastroenterol 2012 107(11)1714-24Chey WD et al Am J Gastroenterol 2012 Nov107(11)1702-12 49
Constellareg - Significant sustained improvement in bowel functioning
50
IBS-C Study 2
Chey WD et al Am J Gastroenterol 2012 Nov107(11)1702-12
bull 76 of linaclotide-treated patients experienced a weekly increase of ge 1 SBMweek(vs 46 of placebo treated patients Plt00001)
bull 54 had an increase of ge 3 SBMsweek (vs15 of placebo treated patients Plt00001)
Mean SBM week p lt 00001 for each of the 26 weeks based on ANCOVA at each weekSBM = spontaneous bowel movement
Week
SBM
W
eek
Chart1
Sheet1
Constellareg - Significant sustained improvement in abdominal pain
IBS-C Study 2
Week
C
hang
e in
Wor
st A
bdom
inal
Pai
n
Least-squares mean percent change in worst abdominal pain p lt 0001 for each of the 26 weeks based on ANCOVA at each week
Chey WD et al Am J Gastroenterol 2012 Nov107(11)1702-12Castro et al Gastroenterol 2013 1451334-1346
bull 70 of linaclotide-treated patients had a clinically relevant reduction in abdominal pain (vs ~50 of placebo treated patients Plt0005)
51