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American Gastroenterological Association Institute Technical Review on the Pharmacological Management of Irritable Bowel Syndrome: An Update for 2019

Lin Chang, MD, AGAF1 Anthony Lembo, MD, AGAF2 Shahnaz Sultan MD, MHSc, AGAF3 1. G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian

Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02214 3. Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN 55455 Address for Correspondence: Chair, Clinical Guidelines Committee, American Gastroenterological Association National Office, 4930 Del Ray Avenue Bethesda, Maryland 20814 E-mail: [email protected] Telephone: (301) 941-2618 Manuscript Word Count: References: Tables and Figures: eTables and eFigures (in the supplement) Keywords: irritable bowel syndrome, treatment, symptoms, quality of life, randomized controlled trials, meta-analysis, linaclotide, plecanatide, lubiprostone, polyethylene glycol, anti-diarrheals, rifaximin, eluxadoline, alosetron, antispasmodics, tricyclic antidepressants, selective serotonin reuptake inhibitors Disclosures and Conflicts of Interest: Lin Chang has served as a member of the scientific advisory board for Alnylam, Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, and Synergy. She has served as a consultant for Allergan. She has received research support from the National Institute of Health, Ardelyx, Alnylam and Vanda. Anthony Lembo has served as a member of the scientific advisory board for Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, Shire, Allergan and Vanda. Shahnaz Sultan is supported by the National Heart, Lung, and Blood Institute at the National Institute of Health for Asthma Guideline Development. She has received research support from the Veterans Affairs Health Care System Health Services Research and Development VA Career Development Award. Acknowledgements: The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.

mailto:[email protected]

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INTRODUCTION

Irritable Bowel Syndrome (IBS) is a common functional gastrointestinal disorder, which

affects approximately 11% of adults.1 IBS affects individuals regardless of race, age or sex though it

is most common in women and younger individuals. Though not a life-threatening condition, IBS is

associated with significant disease burden including decrease in quality of life (QOL), elevated rates

of psychological comorbidities, and high economic costs.2-5 Patients with IBS have worse health-

related QOL than patients with diabetes or end-stage renal disease. The impact of IBS on daily

functioning can be demonstrated by high rate of absenteeism (average of 13.4 days of work or

school per year, compared to 4.9 days for those without IBS) and presenteeism (87% report

reduced productivity at work in the past week resulting in nearly 14 hours per week of lost

productivity due to IBS).6-8 Socially, the impact of IBS on daily life can be seen in the negative

impact of eating outside the home, going out with friends, traveling, and going to new or unfamiliar

places.9, 10 The IBS in America survey conducted by the American Gastrointestinal Association

(AGA) found that IBS with diarrhea (IBS-D) was associated with more avoidance of activities

outside of the home (e.g. travel, making plans, leaving the house, going places without easily

accessible bathrooms). IBS with constipation (IBS-C), on the other hand, was associated with more

interpersonal impairment (e.g. feeling self-conscious, avoiding sex, difficulty concentrating, not

feeling able to reach one’s full potential).11

Since the AGA published the first IBS technical review and guidelines in 2014,12, 13 new

pharmacological treatments have become available and new evidence has accumulated about

established treatments. New treatments approved by the Food and Drug Administration (FDA)

include plecanatide, a guanylate cyclase C agonist, for IBS-C and eluxadoline and rifaximin for IBS-D.

The 2014 technical review12 included data on the phase 3 rifaximin trials for IBS-D since rifaximin

was already FDA approved for hepatic encephalopathy and traveler’s diarrhea. The current

technical review also includes a new phase 3 trial with linaclotide and a retreatment with rifaximin.

Based on this new information, the AGA Clinical Guidelines Committee recommended an update of

the existing technical review and guideline of the newer pharmacologic treatments of IBS.

Objective of this Technical Review Update

This technical review examines the evidence for pharmacologic therapies for treatment of adults

with IBS. In this update of the 2014 technical review, the following new clinical questions were

considered (see Table 1):

• In patients with IBS-C, what is the efficacy and safety of linacotide ?

• In patients with IBS-C, what is the efficacy and safety of plecanatide?

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• In patients with IBS-D, what is the efficacy and safety of eluxadoline?

• In patients with IBS-D who relapse after initial response to rifaximin, what is the efficacy

and safety of rifaximin re-treatment?

The following questions from the previous technical review were also reviewed to determine if

there was any new data:

• In patients with IBS-C, what is the efficacy and safety of lubiprostone or PEG-laxatives?

• In patients with IBS-D, what is the efficacy and safety of rifaximin, alosetron or loperamide?

• In patients with IBS, what is the efficacy and safety of tricyclic antidepressants (TCAs),

serotonin reuptake inhibitors (SSRIs), and antispasmodics?

This technical review and accompanying guideline were developed using the Grading of

Recommendations Assessment, Development and Evaluation (GRADE) framework. The technical

review panel consisted of two content experts with expertise in IBS (A. Lembo and L. Chang) and a

guideline methodologist with expertise in evidence synthesis and use of the GRADE framework (S.

Sultan). Conflicts of interest were managed according to AGA policies and Institute of Medicine

(IOM) and Guidelines International Network (GIN) standards and are presented at the end of this

manuscript. The guideline methodologist had no conflicts of interest. The panel used the GRADEpro

Guideline Development Tool (https://gradepro.org) and created evidence profiles for each

question.14

METHODS

Formulation of clinical questions and determining outcomes of interest

The PICO format was used to outline the specific patient population (P), intervention (I),

comparator (C), and outcome(s) for each clinical question. We focused on adults (18 years of age

and older) with IBS using symptom-based diagnostic criteria and the interventions included were

eluxadoline, plecanatide, rifaximin, and linaclotide (for the new clinical questions) and

lubiprostone, PEG-laxatives, alosetron, rifaximin, loperamide, TCAs, SSRIs, and antispasmodics

(from the 2014 technical review). The panel selected desirable (benefits) and undesirable (harms)

patient-important outcomes that were consistent with the prior technical review. Only CRITICAL

and IMPORTANT outcomes (for decision-making) were summarized in the evidence profiles. FDA

responder outcome for IBS-C and IBS-D were considered to be CRITICAL outcomes. However,

when the FDA responder was not available Adequate Global Relief was considered to be a CRITICAL

https://gradepro.org/

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outcome. For IBS-C, the FDA responder was defined as a participant who reports both a ≥ 30%

reduction in average daily worst abdominal pain scores and an increase of ≥ 1 complete

spontaneous bowel movement (CSBM) per week when compared to baseline for ≥ 6 of 12 weeks.

For IBS-D, the FDA responder was defined as a participant who reports both a ≥ 30% reduction in

average daily worst abdominal pain scores and a ≥ 50% reduction in number of days per week with

at least one stool that has a consistency of Type 6 or 7 by the Bristol Stool Form Scale (BSFS)

compared with baseline. The following outcomes were considered IMPORTANT outcomes:

abdominal pain response, CSBM response, improvement in IBS-QOL (quality of life), improvement

in stool consistency, urgency, and bloating. No minimal clinical important threshold has been

established for improvement in stool consistency, urgency or bloating. For IBS-QOL score, the range

is 0 and 100 and a MID is 14. 15 Undesirable outcomes included adverse effects leading to treatment

discontinuation. The minimal clinically meaningful improvement (often referred to as the smallest

difference that patients care about) was defined as an improvement in an outcome of 10% or

greater by the authors (consistent with the prior technical review).

Information Sources and Study Selection

An experienced medical librarian performed a systematic literature search of multiple electronic

databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, EMBASE, and

Wiley Cochrane Library) using a combination of controlled vocabulary terms supplemented with

keywords. The search was conducted on [ADD DATE]. For evidence synthesis, randomized

controlled trials (RCTs) conducted in adults with IBS evaluating interventions of interest

(corresponding to relevant PICOs) were included. Details of the search strategy are reported in the

Online Supplement.

Data Extraction and Statistical Analysis

Data abstraction was conducted in single, independently, by one investigator (SS) with any questions

of accuracy resolved by discussion and consensus with the technical review team. If results were

incomplete or unclear, study authors or study sponsors were contacted for additional information.

Outcomes were abstracted and reported as failure of symptom relief (FDA responder), failure of

abdominal pain response, failure of CSBM response, failure of improvement in stool consistency,

bloating, or urgency, failure to achieve a clinically meaningful improvement in IBS-QOL, adverse

events leading to treatment discontinuation or other harm outcomes. For one of the interventions,

rifaximin re-treatment, two additional outcomes were also included: failure to prevent recurrence,

failure of a durable response. All analyses were conducted using true intention-to-treat analysis.

Pooled relative risk (RR) or odds ratios (OR) and 95% confidence intervals (CI), were calculated using

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the Mantel-Haenszel fixed-effects model (in the absence of conceptual heterogeneity and if <3

studies) or the DerSimonian-Liard random-effects model.16 Statistical heterogeneity was assessed

using the I2 statistic. Small study effects were examined using funnel plot symmetry and Egger’s

regression test, though it is important to recognize that these tests are unreliable when the number

of studies is <10. Direct comparisons were performed using RevMan v5.3 (Cochrane Collaboration,

Copenhagen, Denmark). To ensure that recent studies were not missed, searches were updated prior

to the public comment and panel members were asked to suggest any studies that may have been

considered missed and fulfilled the inclusion criteria for the individual questions.

Certainty or Quality of the Evidence

Evidence profiles were used to display the summary estimates as well as the judgments about the

overall quality of body of evidence for each clinical question. The certainty of the body of evidence

(also known as quality of the evidence) was assessed for each effect estimate of the outcomes of

interest following the GRADE approach based on the following domains: risk of bas, precision,

consistency and magnitude of the estimates of effect, directness of the evidence, risk for publication

bias, presence of large effects, dose-response relationship, and an assessment of the effect of

plausible residual and opposing confounding. Within the GRADE framework, randomized

controlled trials (RCTs) start as high-quality evidence and observational studies start out as lo-

quality evidence but can be rated down for the 5 possible reasons: risk of bias, inconsistency,

indirectness, imprecision, and publication bias. Additionally, well-done observational studies start

can be rated up for large effects, dose-response and residual confounding) (see Glossary of Terms

in Supplementary Methods). Judgments about the certainty were determined via telephone

discussion and consensus. The certainty of evidence was categorized into 4 levels ranging from very

low to high (see Table X). For each question, an overall judgment of certainty of evidence was made

for the critical outcomes.

RESULTS

Question: Should Linaclotide Be Used in Patients With IBS-C?

Linaclotide is a non-absorbed 14-amino acid peptide that stimulates the guanylate cyclase C (GC-C)

receptor on enterocytes. Activation of the GC-C receptor results in intestinal chloride and

bicarbonate secretion via the secondary messenger cyclic guanosine monophosphate (cGMP),

which activate the cystic fibrosis transmembrane conductance regulator (CFTR) and, in animal

models, inhibits colonic nociceptors.17-19 Linaclotide is FDA approved for the treatment IBS-C at a

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dose of 290 mcg once daily, and for chronic idiopathic constipation (CIC) at doses of 72 mcg and

145 mcg once daily.

Summary of the Evidence

The 2014 technical review reported on data from 3 RCTs (2 Phase 3 RCTs and 1 Phase 2b RCT)20-22

that included 1773 IBS-C patients (linaclotide n= 890; placebo, n=883). Since 2014, a third 12-

week Phase 3 trial23 has been published that included 839 patients (mean age = 41 years; 82%

female) from China (79%), Oceania (5%) and North America (16%). In contrast to the previous

trials which used Rome II criteria for IBS,24 this trial included patients who met the Rome III IBS

criteria.25 To be included in this study patients were required to report (during the 2-week baseline

period) an average of ≤ 5 spontaneous BMs (SBMs) per week and < 3 complete SBMs (CSBMs per

week and had to report abdominal pain ≥ 2 days each week with an average score ≥ 3.0 on a 0- to

10-point numerical rating scale (0 indicating no pain and 10 the worst imaginable pain). Patients

were excluded if they reported BSFS score of 6 for > 1 SBM or 7 for any SBM. There were 2 co-

primary responder endpoints that consisted of improvement in weekly abdominal pain or

abdominal discomfort score and in weekly IBS degree of relief score for ≥ 6 of 12 weeks (Table 2).

Benefits

In the third Phase III trial, 23 60.0% of patients receiving linaclotide reported ≥ 30% reduction in

abdominal pain/discomfort compared with 48.8% of patients receiving placebo and 31.7% of

patients receiving linaclotide reported a an IBS degree of relief score of ≤ 2 compared with 15.4% of

patients receiving placebo. In addition, the FDA endpoint for IBS-C (Table 2) was met by 34.8% in

the linaclotide group vs. 21.3% in the placebo group, which was similar to previous trials.20, 21

The overall efficacy of linaclotide was re-analyzed using data from this new study. Across the 4

RCTs, a total of 1307 patients were treated with linaclotide 290 mcg and 1305 with placebo.

Compared to placebo, patients who received linaclotide 290 mcg had greater symptom relief using

the FDA responder endpoint for IBS-C (relative risk (RR) 0.81; 95% CI 0.77 to 0.85). Similarly,

compared to placebo, patients who received linaclotide showed greater improvement in the global

assessment measuring adequate relief of IBS-C symptoms over the first 12 weeks (RR 0.71; 95% CI

0.67 to 0.76).

With respect to individual symptoms, a greater proportion of patients who were treated with

linaclotide were abdominal pain responders (RR 0.83; 95% CI 0.78 to 0.88) and CSBM responders

(RR 0.86, 95% CI, 0.83 to 0.89) compared to placebo over the initial 12 weeks.

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Harms

Diarrhea was the most common adverse event occurring in 13.5% of patients receiving linaclotide

compared to 2.3% of patients receiving placebo. Linaclotide was associated with more

discontinuations (3.4%) compared to placebo (0.2%) (RR 14.94; 95% CI, 4.65 to 48.03) with

diarrhea being the most common reason for discontinuation. No serious adverse events due to

diarrhea were reported in any of the trials.

Certainty in Evidence of Effects

There was a low risk of bias and no evidence of imprecision or serious indirectness. We rated down

for inconsistency for the following outcome: IBS-QOL. The overall certainty in evidence for

linaclotide was HIGH. See Table 3 for the full evidence profile.

Discussion

The addition of a third phase III trial,23 which was performed predominantly in China, supports the

efficacy of linaclotide for the treatment of IBS-C. The beneficial effects on linaclotide across all

outcomes was very similar to that found in our prior technical review which did not include this

third phase III trial. Linaclotide improved global assessment of IBS-C symptoms (FDA responder,

adequate global response) as well as key symptoms of IBS-C including abdominal pain and CSBM.

The recent meta-analysis and systemic review of IBS treatments by the American College of

Gastroenterology (ACG) IBS Task Force only evaluated the efficacy of linaclotide on overall

symptom improvement but similarly rated the quality of evidence as high.26 A recent network

meta-analysis ranked linaclotide first in efficacy among secretatogues for IBS-C,27 though head to

head trials are lacking. The rate of diarrhea reported with linaclotide was 13.5% and resulted in

discontinuation in 3.4%. No serious adverse events due to diarrhea were reported in any of the

trials. It is worth noting in the third phase III trial,23 fewer patients reported diarrhea (9.4%) and

the withdrawal rate from diarrhea was lower (0.7%) than in previous RCTs with linaclotide.

Although diarrhea was more commonly reported with linaclotide than reported by other

secretogogues, particularly plecanatide, which is also a GC-C receptor agonist, a meta-regression

analysis, which controlled for differences in diarrhea rates in the placebo arm, found the rate of

diarrhea and diarrhea-related withdrawals was similar between the two GC-C agonists.28

Question: Should Plecanatide Be Used in Patients With IBS-C?

Plecanatide is a non-absorbed 16 amino-acid peptide structurally similar to uroguanylin which, like

linaclotide, stimulates the GC-C receptor causing fluid and electrolyte secretion29 and reducing

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visceral hypersensitivity in an animal model.30 In contrast to linaclotide which is not pH sensitive,

plecanatide has a higher affinity to the GC-C receptor in the more acidic environment seen in

proximal duodenum. Plecanatide is approved for the treatment of IBS-C and CIC at a dose of 3 mg

once daily in the U.S.


In two large phase III trials,31 the efficacy of two doses of plecanatide (3 mg and 6 mg once daily)

were assessed over 12 weeks in patients with IBS-C. Patients included in these trials met Rome III

criteria for IBS-C 32 and reported no more than 3 CSBMs or > 6 SBMs per week, and an average

worst abdominal pain score of > 3 on a scale of 0 to 10 (0 indicating no pain and 10 the worst

imaginable pain). Patients could not report a worst abdominal pain score of 0 for more than 2 days

or BSFS score of 7 for 1 or more days or a BSFS33 score of 6 for more than 1 day. The primary

efficacy responder definition was the FDA responder endpoint34 which is shown in Table 4 along

with the abdominal pain and CSBM responder definitions. A phase IIb dose ranging trial published

only in abstract form was also included as it contained a 3 mg treatment arm.35

Benefits

In total, 814 IBS-C patients were treated with plecanatide 3 mg and 818 were treated with

placebo. Compared to placebo, patients who received plecanatide 3 mg showed greater symptom

relief using the FDA responder endpoint for IBS-C (RR 0.87; 95% CI 0.83 to 0.92). Plecanatide was

associated with a 27.4% FDA endpoint responder rate compared to a 16.9% responder rate with

placebo. With respect to individual symptoms, plecanatide demonstrated a higher success rate of

over the initial 12 weeks compared to placebo for improvement in abdominal pain (RR 0.86; 95%

CI 0.81 to 0.92) and CSBM (RR 0.84, 95% CI, 0.79 to 0.91).

Harm

Approximately 3.1% of patients treated with plecanatide (3 and 6 mg) and 0.5% of patients treated

with placebo discontinued therapy due to adverse events. Diarrhea was the most common adverse

event. In the Phase III trials diarrhea was reported by 4.3% of patients receiving plecanatide

compared to 1% of patients receiving placebo. Diarrhea led to discontinuation in 1.2% of patients

receiving plecanatide 3 mg compared to 0% receiving placebo. No serious adverse events were

diarrhea-related. As discussed above, based on a meta-regression analysis, which controlled for

diarrhea events in the placebo, the odds of developing diarrhea or withdrawing due to diarrhea

with plecanatide was similar to linaclotide.28


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We rated down for imprecision across many of the outcomes because the lower boundary of the

confidence interval crossed our threshold of a clinically meaningful difference. The trials were

considered to be low risk of bias. The overall certainty in evidence for plecanatide was

MODERATE. See Table 5 for the full evidence profile.

Discussion

Plecanatide treatment resulted in greater improvement in the FDA endpoint for IBS-C, as well as

the components of the FDA endpoint (i.e, abdominal pain and CSBM response). However, the

improvement in these endpoints may be small in some patients since the lower boundary of the

confidence interval crossed our threshold of a clinically meaningful difference. While not included

in the evidence profiles, plecanatide was associated with improvement in important endpoints

including stool frequency, bloating, straining and global measures of treatment satisfaction

compared with placebo.31 The ACG IBS Task Force also rated the quality of evidence for

plecanatide as moderate.26 Plecanatide was generally well tolerated; 1.2% of patients withdrew

from the trials due to diarrhea from plecanatide. As previously mentioned, RCTs with linaclotide

reported higher rates of withdrawal from diarrhea, however, the odds of developing diarrhea

compared to placebo with these agents is similar.28

Question: Should Eluxadoline Be Used in Patients With IBS-D?

Eluxadoline is a minimally absorbed mixed μ- and -opioid receptor agonist and δ-opioid receptor

antagonist that was developed to reduce constipation and increase analgesic potency compared to

pure μ-opioid agonist.36, 37 Eluxadoline is approved for the treatment of IBS-D at a dose of 100 mg

twice daily in the U.S., Canada and Europe. Eluxadoline 75 mg twice daily is recommended in

patients who are unable to tolerate the 100 mg dose, who mild or moderate hepatic impairment or

who are receiving concomitant OATP1B1 inhibitors.


In two large phase III trials, eluxadoline 75 and 100 mg twice daily were assessed over 26 weeks in

patients with IBS-D.38 Patients were eligible if they met Rome III criteria for IBS-D32 and had an

average worst abdominal pain score of > 3 (on a scale of 0 to 10, with 0 indicating no pain and 10

the worst imaginable pain), an average score for stool consistency of > 5.5 on the BSFS,33 a BSFS

score of > 5 for at least 5 days, and an average IBS-D global symptom score of > 2 (on a scale of 0 to

4, with 0: no symptoms and 4: very severe symptoms). Exclusion criteria included a history of

pancreatitis and Sphincter of Oddi dysfunction, alcohol abuse, and post-cholecystectomy biliary

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pain. The FDA responder outcome was assessed over weeks 1-12 or while the European Medicines

Agency (EMA) endpoint was assessed over weeks 1-26 (Table 6).

Benefits

In the two phase 3 trials, 808 patients were randomized to eluxadoline at 100 mg and 809 were

given placebo twice daily.38 Compared to placebo, a greater proportion of patients who received

eluxadoline were FDA endpoint responders (relative risk (RR) 0.87; 95% CI 0.83 to 0.92) and EMA

endpoint responders (RR 0.86; 95% CI 0.81 to 0.91) compared to placebo. These studies also used a

global assessment measuring adequate relief of IBS-D symptoms. Compared to placebo, a greater

proportion of patients who received eluxadoline reported adequate relief for > 6 out of the first 12

weeks (RR 0.87; 95% CI 0.81 to 0.93).

With respect to individual symptoms, during the initial 12 weeks eluxadoline may be associated

with a small improvement in abdominal pain (RR 0.92; 95% CI 0.84 to 1.00). Compared to placebo

during the initial 12 weeks eluxadoline was associated a clinically significant improvement in stool

consistency (RR 0.84; 95% CI, 0.80 to 0.88) and compared to placebo, a greater proportion of

patients taking eluxadoline had 50% urgency-free days (RR 0.84, 95% CI, 0.78 to 0.90).

Finally, a greater proportion of patients receiving eluxadoline achieved a clinically meaningful

improvement in IBS-QOL compared to placebo during the initial 12 weeks (RR 0.84; 95% CI 0.74 to

0.95). Similar results for all endpoints were seen in weeks 1-12 and 1-26.

Harm

Approximately 8% of patients treated with eluxadoline (75mg or 100mg) and 4% of patients

treated with placebo discontinued therapy due to adverse events. The most common adverse

events were constipation, nausea, and abdominal pain. There were 5 pancreatitis (RR =-5.34; 95%

CI, 0.30 to 96.42) and 8 Sphincter of Oddi dysfunction events in the eluxadoline group (RR 8.25,

95% CI, 0.48 to 142.76) and none in the placebo group. These cases were associated with the

absence of a gallbladder or history alcohol abuse. For this reason, eluxadoline is contraindicated in

patients without a gallbladder or those who drink more than 3 alcoholic beverages per day.



confidence interval crossed our threshold of a clinically meaningful difference and range of possible

effects included benefits that may not be meaningful to patients. The overall certainty in

evidence of effects for eluxadoline was MODERATE. See Tables 7 and 8 for the full evidence

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profiles.

Discussion

Evidence supports the efficacy of 100 mg of eluxadoline in IBS-D based on two phase III RCTs.38

While eluxadoline was associated with a significantly greater proportion of patients meeting the

FDA endpoint for IBS-D and also adequate global relief of IBS symptoms compared to placebo, the

improvement may be small in some patients. However, eluxadoline was associated with clinically

meaningful improvements in stool consistency and urgency in IBS-D, but it had less effect on

abdominal pain. Thus, eluxadoline may be more ideal in IBS-D patients with predominant and

bothersome diarrhea than those with predominant or more severe abdominal pain. The symptom

benefits of eluxadoline translated to a significant proportion of patients reporting clinically

significant improvement in IBS-related quality of life. Eluxadoline 100 mg twice daily is

recommended in most patients, although very similar beneficial effects were found with the 75 mg

dose of eluxadoline. With regard to adverse events, eluxadoline was associated with an increased

risk of pancreatitis, which was considered a critical outcome, and Sphincter of Oddi dysfunction.

These adverse events occurred in patients without a gallbladder and with respect to pancreatitis, a

history of alcohol abuse. Thus, eluxadoline is contraindicated in patients without a gallbladder and

excessive alcohol abuse as well as a history of Sphincter of Oddi disease or dysfunction,

pancreatitis, bile duct obstruction, and severe liver impairment.39 The ACG IBS Task Force similarly

rated the quality of evidence for eluxadoline as moderate.26

Question: Should Rifaximin Be Used for Retreatment in Patients With IBS-D?

Rifaximin is a broad spectrum, non-systemic antibiotic that is FDA approved for treatment of IBS-D

in United States. In the 2014 technical review, we assessed the quality of evidence of three RCTs,

including two phase III trials, comparing a 14-day course of rifaximin 550 mg TID vs. placebo for

the treatment of non-constipated IBS. We rated the quality of evidence as moderate.12 In an effort

to evaluate the post-treatment effect of rifaximin beyond the 10 weeks of these pivotal RCTs, a

subsequent placebo-controlled, 51-week, phase III RCT was conducted to assess the efficacy and

safety of repeat treatment after clinical response and subsequent symptom relapse with rifaximin

for IBS-D.40


In the phase III retreatment trial with rifaximin,40 IBS-D patients who met Rome III diagnostic

criteria25 and had baseline abdominal pain and bloating scores of > 3 (on a scale of 0 to 10, with 0

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indicating no pain and 10 the worst imaginable pain) and loose stools of > 2 days per week (i.e.,

Bristol Stool Form Scale [BSFS]33 type 6 or 7) were enrolled. A single-blind, baseline screening

phase of placebo for 10 days was conducted to remove placebo responders. Patients then entered

an open-label treatment phase with rifaximin 550 mg TID for 2 weeks. A responder was defined as

simultaneous improvement in both abdominal pain (>30% decrease from baseline in pain score)

and stool consistency (>50% increase from baseline in number of days/week with BSFS type 6 or

7) during >2 of the 4 weeks after treatment (Table 9). This endpoint is equivalent to the FDA

endpoint for IBS-D though only for 4 weeks. Responders were observed for up to 18 additional

weeks or until symptom relapse occurred. Relapse was defined as a loss of treatment response for

either weekly abdominal pain (<30% decrease from baseline in mean weekly pain score) or stool

consistency (<50% decrease from baseline in number of days/week with BSFS type 6 or 7 stool) for

3 of 4 consecutive weeks. Initial responders who relapsed were randomized to either two 14 day

repeat treatment courses of rifaximin at 550 mg tid or placebo.

The primary endpoint of this study was the percentage of FDA endpoint responders during the 4-

week after the first repeat treatment (primary evaluation period). The primary endpoint was

considered a CRITICAL outcome. Three additional CRITICAL endpoints were prevention of

recurrence, sustained IBS symptom relief (“durable” response), and bloating response (Table 9).40

IMPORTANT outcomes were adequate relief of abdominal pain, adequate relief of urgency

improvements in stool consistency percentage of patients with clinically meaningful improvement

in IBS-related QOL.

Benefits

In the first repeat treatment phase of the trial, 328 patients were randomized to rifaximin and 308

to placebo three times daily. Compared to those on placebo, a higher proportion of patients who

received rifaximin were FDA outcome responders (39.1% vs. 31.5%, relative risk (RR) 0.90; 95% CI

0.80 to 1.01). A greater proportion of patients on rifaximin did not experience symptom recurrence

throughout the retreatment phase of the study (13.2% vs. 7.1%, RR 0.93; 95% CI 0.88 to 0.99) and

were more likely to have a durable response than patients on placebo (17.1% vs. 11.7%, RR 0.94;

95% CI 0.88 to 1.00).

A greater proportion of IBS-D patients taking rifaximin achieved adequate relief of abdominal pain

compared to patients taking placebo (50.6% vs. 42.2%, RR 0.85; 95% CI 0.74 to 0.99). Compared to

placebo, rifaximin was also associated with a greater proportion of patients reporting adequate

improvement in urgency (48.5% vs. 39.6%, RR 0.85; 95% CI 0.74 to 0.98). Improvements in stool

consistency (51.8% vs. 50%, RR 0.85; 95% CI 0.82 to 1.13) and bloating (46.6% vs. 41.2%, RR 0.85;

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95% CI 0.79 to 1.04) were similar between rifaximin and placebo. Patients on rifaximin were also

more likely to achieve a clinically meaningful improvement in IBS-related QOL compared to placebo

(38.7% vs. 29.5%, RR 0.66; 95% CI 0.48 to 0.92).

Harm

Safety data from the re-treatment study were reported for the open-label cohort and the double-

blind cohort separately. In the open-label population, adverse events were reported in 3.1% of

patients taking rifaximin. In the double-blind population, adverse events were reported in 1.8% of

patients on rifaximin vs 2.6% on placebo. The most common adverse events were nausea, upper

respiratory infection, urinary tract infection and nasopharyngitis. Adverse events leading to study

discontinuation were not reported. One patient developed C. difficile colitis infection 37 days after

repeat treatment with rifaximin. This patient tested negative for C. difficile toxins A and B at study

entry, had a medical history of C. difficile infection, and had completed 10-day course of cefdinir for

a urinary tract infection immediately before development of C. difficile colitis.



confidence interval crossed our threshold of a clinically meaningful improvement. The overall

certainty in evidence of effects for rifaximin was MODERATE. See Table 10 for the full evidence

profile.

Discussion

The evidence supports that retreatment with rifaximin is a safe and efficacious for IBS-D, however

the improvements across outcomes may be small and may not be clinically meaningful. The

certainty in evidence for retreatment with rifaximin is similar to the phase III treatment trials

(Target 1 and 2)41 and compares similarly with efficacy of rifaximin in the 2014 technical review. In

the retreatment trial, rifaximin was associated with a greater durable response and prevention of

symptom recurrence of symptoms and a durable response compared to placebo. In addition, the

efficacy of rifaximin retreatment in improving abdominal pain, urgency, and IBS-related quality of

life was greater in placebo, but its effect on stool consistency and bloating were not. The response

rates with retreatment of rifaximin and placebo were lower than what was demonstrated in the

previous phase III treatment trials. In addition, rifaximin has been shown in these previous trials to

significantly improve bloating compared to placebo, but retreatment with rifaximin did not have a

significant effect on bloating. These differences can be due to several factors. The Target 1 and 2

trials measured the efficacy of an initial course of rifaximin in IBS patients, while the retreatment

trial evaluated efficacy for symptom relapse after an open label course of rifaximin. Thus, patients

14

had a lower severity of symptoms at the onset of the first double-blind treatment phase.40

Furthermore, the retreatment trial was not powered to measure the bloating response. The adverse

event profile of rifaximin was similar to that of placebo. This is supported by a previous study by

Schoenfeld and colleagues.42in which the safety and tolerability of rifaximin in the phase IIb and III

RCTs in non-constipated IBS patients was evaluated. Patients receiving rifaximin (n = 1103) and

placebo (n = 829) had a similar incidence of drug-related adverse events (12.1% vs. 10.7%), serious

adverse events (1.5% vs. 2.2%), drug-related adverse events resulting in study discontinuation

(0.8% vs. 0.8%), gastrointestinal-associated adverse events (12.2% vs. 12.2%) and infection-

associated adverse events (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis, other

than the one patient who developed this > 1month after rifaximin retreatment, or deaths.

Review of Evidence from Prior Technical Review

Evidence for the following interventions was also reviewed: Lubiprostone, PEG-laxatives, Rifaximin,

Alosetron, Loperamide, TCAs, SSRIs, and Antispasmodics.12

Lubiprostone for IBS-C

Lubiprostone is a chloride channel type 2 activator that increases chloride influx into the lumen of

the gastrointestinal tract, resulting in acceleration of intestinal transit.43 Lubiprostone is approved

for the treatment of adult women with constipation-predominant IBS at a dosage of 8 µg twice

daily. It is also approved for the treatment of chronic idiopathic constipation in adult men and

women at a dose of 24 µg twice daily.

Summary of the evidence

No new RCTs of lubiprostone for the management of IBS-C were identified since the 2014 technical

review. As previously reported, we identified 2 identically designed phase 3 RCTs that included

1154 patients with IBS-C.44 Lubipostone was superior to placebo for a modified FDA response (i.e.,

adequate abdominal pain and SBM response; RR, 0.88; 95% CI, 0.79–0.96), adequate global

response, (RR, 0.93; 95% CI, 0.87–0.96) and abdominal pain relief (RR, 0.85; 95% CI, 0.76–0.95),

but not SBM frequency (RR, 0.90, 95% CI, 0.75–1.10). With respect to adverse events leading to

treatment discontinuation, a similar number of patients withdrew in the lubiprostone group

(12.8%) vs placebo (12.3%). Adverse events specifically related to the gastrointestinal tract were

reported in 19% of patients receiving lubiprostone compared with 14% receiving placebo. The

overall certainty in evidence was MODERATE.

Discussion

15

Although there was a significantly beneficial effect of lubiprostone on global outcomes and

abdominal pain response compared with placebo, these differences did not meet the threshold for

being clinically meaningful. Furthermore lubiprostone was not superior to placebo for adequate

SBM response. It is not known if lubiprostone would be associated with an improvement in CSBM

response because CSBM was not measured. Data from a long-term safety extension study in

patients with IBS-C found lubiprostone to be safe and well tolerated for up to 13 months of

treatment.45

PEG Laxatives for IBS-C

PEG is a long-chain polymer of ethylene oxide, which acts as an osmotic laxative and is FDA

approved for the short-term treatment of adults with occasional constipation. PEG without

electrolytes is widely available for the treatment of constipation, including in the US where it is

available over the counter.


No new studies of PEG for the treatment of IBS-C were identified since the 2014 technical review,

which included only one placebo-controlled trial.46 This trial was a 4-week RCT that compared the

efficacy of PEG 3350 in combination with electrolytes (PEG-E, n=68) or placebo (13.8 sucrose with

0.1 g, n=71). Responders were defined as patients with pain reduction of >30%, >3 SBMs per week,

and an increase of 1 SBM per week. In a post-hoc analysis, PEG-E was not associated with symptom

relief based on the responder definition (RR, 0.90; 95% CI, 0.66–1.2) or abdominal pain response

(RR, 0.93; 95% CI, 0.67–1.4). Other important outcomes, including CSBM responders, IBS-QOL and

adverse outcomes were not assessed or not reported. However, there was a significant

improvement in SBM frequency with PEG compared to placebo. Additional limitations of this study

included that it was a single-center study with a relatively short duration of treatment for an IBS

clinical trial and used varying treatment doses per patient. The overall certainty in evidence for

PEG laxatives was LOW.

Discussion

In clinical practice, PEG is commonly used for chronic constipation and has been shown to be

efficacious;47 however, its effects on symptoms of IBS have not been well studied. Chapman et al. 46

did not show a statistically significant or clinically meaningful improvement in abdominal pain or in

the modified FDA responder end point for IBS-C in patients receiving PEG-E compared with

placebo. Although this study showed a statistically significant improvement of CSBM frequency

with PEG-E compared with placebo, the response rates could not be calculated based on the

available data. A more comprehensive assessment of PEG’s efficacy in IBS-C could not be obtained

16

due to having only one RCT that was comprised of a relatively small number of IBS patients

compared to multicenter RCTs.

Although PEG has been shown to improve symptoms of constipation, larger high-quality studies are

clearly needed to adequately evaluate the efficacy of PEG in patients with IBS-C in whom abdominal

pain is a more predominant symptom.

Rifaximin for IBS-D

In the 2014 technical review,12 the efficacy of rifaximin in non-constipated IBS was evaluated. In

contrast to the current technical review, which examines the efficacy of rifaximin re-treatment in a

uniquely designed RCT (see above).


In the 2014 technical review, three RCTs in 1258 patients (rifaximin 624; placebo 634) compared

rifaximin vs. placebo for the treatment of non-constipated, Rome II positive IBS patients.41, 48 The

dose of rifaximin in the studies was 550 mg three times a day for two weeks. Efficacy endpoints

were assessed during the 4 weeks after completing two weeks of treatment with rifaximin. The FDA

Responder endpoint for IBS-D was evaluated only in the two phase III clinical trials. Compared to

placebo, rifaximin had a significantly greater response based on the FDA responder endpoint for

IBS-D (RR 0.85; 95% CI 0.78 to 0.94). Compared to placebo, rifaximin was also superior with

respect to adequate relief of global relief and discomfort (RR 0.87, 95% CI 0.80 to 0.94). In the

phase III trials, rifaximin was associated with a greater improvement in the relief of bloating (RR

0.86, 95% CI 0.70 to 0.93) and abdominal pain (RR 0.87, 95% CI 0.80 to 0.95). Outcomes including

SBM frequency, CSBM responder rate, HR-QOL improvement and diarrhea leading to treatment

withdrawal could not be assessed based on the available data. The overall certainty in evidence

for rifaximin was MODERATE.

Discussion

The three placebo-controlled RCTs supported the efficacy of rifaximin in patients with IBS-D based

on the composite end point of improvement of abdominal pain and stool consistency, adequate

global relief, abdominal pain, and bloating. However, the CIs of the outcomes crossed our minimal

clinically important threshold of 10%, and therefore we rated down for imprecision. While the

study population was comprised of non-constipated IBS patients, they were predominantly IBS-D.

The duration of rifaximin treatment course and endpoint assessment differs from other IBS

treatments as it was given daily for only 14 days and the endpoints were assessed during the 4

weeks that followed completion of the treatment. The efficacy of rifaximin appeared to possibly

17

diminish over time and therefore repeated treatment was assessed in the subsequent clinical trial

prior to its approval by the FDA.

Alosetron for IBS-D

Alosetron is a selective 5-HT3 antagonist, with a mechanism of action that is believed to be both

centrally and peripherally mediated.49 Alosetron was originally approved by the FDA in 2000 for

the treatment of IBS-D in women; however, it was voluntarily withdrawn due to serious adverse

events, namely ischemic colitis and serious complications of constipation. In 2002, the FDA

approved the reintroduction of alosetron but restricted its use to the treatment of severe IBS-D in

women under a risk management program.50


No new studies of alosetron for the management of IBS-C were identified since the 2014 TR.

Evidence to support the use of alosetron comes from 8 RCTs in 4227 patients (alosetron, n=2517;

placebo, n=1710) that compared the efficacy of alosetron with placebo in patients with

nonconstipating IBS.51-58 Seven of the 8 studies evaluated the efficacy of alosetron over a 12-week

period, and the remaining study was a 48-week trial. Alosetron was superior to placebo in

improving global symptoms (RR, 0.60; 95% CI, 0.54–0.67), and IBS pain and discomfort (RR, 0.83;

95% CI, 0.79–0.88). Additionally, the individual studies showed that alosetron was shown to

improve urgency, stool consistency, and IBS-QOL. With respect to adverse events, a postmarketing

study evaluating the safety of alosetron over 9 years showed that the cumulative adjudicated

incidence of ischemic colitis was 1.03 cases per 1000 patient-years and the adjudicated incidence

rate of serious complications of constipation was 0.25 cases per 1000 patient-years and appeared

to have declined over time. 50 The overall certainty in evidence for alosetron was MODERATE.

Discussion

Alosetron is indicated in women with IBS-D who have not responded to conventional therapy and

have symptoms that are severe, which is defined as one or more of the following: frequent and

severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, and/or disability

or restriction of daily activities due to IBS. There is moderate to high-quality evidence that

alosetron improves symptoms of IBS compared with placebo, but careful selection of patients and

education about the risks and benefits of alosetron are vital. Of note, the 9-year follow-up data on

the postmarketing safety of alosetron under the risk management program have shown that the

incidence of complications of constipation has declined while that of ischemic colitis has remained

stable.50

18

Loperamide for IBS-D

Loperamide a synthetic peripheral opioid receptor agonist; it inhibits peristalsis and antisecretory

activity and prolongs intestinal transit time with limited penetrance of the blood-brain barrier. It is

FDA approved for the treatment of patients with acute, chronic, and traveler’s diarrhea.


No new studies have evaluated the efficacy of loperamide in the management of patients with IBS.

Two small, double-blind, placebo controlled trials have evaluated the efficacy of loperamide in

patients with IBS.59, 60 Neither defined the diagnostic criteria for IBS but excluded organic

gastrointestinal disease. Compared with placebo, loperamide was associated with adequate relief of

abdominal pain (RR, 0.41; 95% CI, 0.20–0.84), improvement in stool consistency (RR, 0.06; 95% CI,

0.01–0.43) and global improvement in symptoms (RR, 0.73; 95% CI, 0.29–1.86). No improvement in

urgency symptoms was noted and there was no data on IBS-QOL or adverse events. The overall

certainty in evidence for loperamide was VERY LOW.

Discussion

There was a lack of beneficial effect on global improvement of symptoms of IBS and urgency but

improvement in abdominal pain and stool consistency. Improvements in these symptoms occurred

within 3 to 5 weeks of starting treatment, and details of how this was determined were poorly

described. However, this review was based on only 2 very small studies. Both studies were

published in 1987 and were conducted at a time when there was less guidance on the conduct of

high-quality clinical trials. Loperamide has proven efficacy in reducing diarrhea, but there is a lack

of data evaluating its efficacy in relieving individual gastrointestinal symptoms, such as abdominal

pain, in IBS. It is also not clear if loperamide should be only recommended in IBS-D or also in IBS-M,

presumably during a diarrheal phase. The optimal dose and method of using loperamide (e.g., as

needed, daily, after a certain number of diarrheal stools, etc.) is not known and potentially can vary

between patients based on their symptom patterns.

Tricylic antidepressants (TCAs) for IBS

TCAs have been used to treat IBS symptoms due to their peripheral and central (i.e., supraspinal

and spinal) actions which can affect motility, secretion and sensation. IBS and other functional GI

disorders have been redefined in Rome IV as disorders of gut-brain interactions, characterized by

any combination of motility disturbance, visceral hypersensitivity, altered mucosal and immune

function, altered gut microbiota, and altered central nervous system (CNS) processing.61 Consistent

with this redefinition and based on the fact that TCAs and other antidepressants have physiologic

19

effects separate from the effect on mood, these agents have been relabeled as gut-brain

neuromodulators.62


The efficacy of TCAs in IBS was previously evaluated in the prior technical review based on eight

placebo-controlled RCTs in 523 patients (TCAs 297; placebo 122).12 All but one study enrolled

multiple IBS bowel habit subtypes. The type of TCA studied included amitriptyline (n=3),

desipramine (n=2), trimipramine (n=1), imipramine (n=1), and doxepin (n=1). The dose of the TCA

varied from 10 mg to up to 150 mg and most studies used greater than 50 mg per day. Global

assessments differed among the trials and abdominal pain response was assessed in 4 trials.

Compared to placebo, TCAs were associated with global symptom relief (RR 0.67; 95% CI 0.54 to

0.82) and abdominal pain relief (RR 0.76 to 0.94). However, the quality of evidence was rated

down due to indirectness, risk of bias, and imprecision. Based on data from 22 clinical trials in

depression (as long-term high quality data on adverse events with TCAs in IBS was not available),

TCAs showed a significantly higher rate of withdrawals due to side effects compared to placebo (RR

2.11; 95% CI 1.35 to 3.28). The overall certainty in evidence for TCAs was LOW.

Discussion

TCAs were associated with greater responses of adequate relief and abdominal pain relief

compared to placebo, however only global relief response met the threshold for being clinically

meaningful. The beneficial effects of TCAs on IBS symptoms appear to be independent of effects on

depression and may take several weeks. Most studies evaluated higher doses of TCAs (i.e. 50 mg

and higher) than those used in clinical practice. There was one study demonstrating that

amitriptyline 10 mg at bedtime had greater efficacy that placebo in patients with IBS-D.63 TCAs have

multiple actions including inhibition of serotonin and noradrenergic reuptake and blockade of

muscarinic 1, 1 adrenergic, and histamine 1 receptors.62 These effects are beneficial (e.g., reduce

diarrhea and abdominal pain) but also can cause adverse events (e.g. dry mouth, sedation and

constipation). Therefore, the selection of TCA should be based on the patient’s symptom

presentation.

Selective serotonin reuptake inhibitors (SSRIs) for IBS

SSRIs are approved for the treatment of mood disorders, such as anxiety and depression, but are

also used in clinical practice to treat chronic pain conditions. SSRIs selectively inhibit the reuptake

of 5-HT at presynaptic nerve endings, which results in an increased synaptic concentration of 5-HT.

The use of SSRIs in IBS has been of significant interest since IBS is considered a brain-gut disorder

and these agents have centrally mediated effects and increase gastric and intestinal motility,

20

although they do not appear to have a major impact on visceral sensation.62


The efficacy of SSRIs in IBS was studied in seven RCTs,63-69 Most of the studies enrolled a mixture of

all three main bowel habit subtypes. Patients with current psychiatric disease were generally

excluded. Duration of treatment ranged from 6 weeks to 12 weeks. Different SSRIs were evaluated:

fluoxetine 20 mg daily,63, 65 paroxetine 10 mg daily that could be increased,70 paroxetine-CR 12.5-50

mg daily67 and three studies used citalopram at a starting dose of 20 mg that was increased to 40

mg daily after two,69 three,64 or four66 weeks. Compared to placebo, SSRIs showed possible

improvement in symptom relief (RR 0.74; 95% CI 0.52 to 1.06) and in abdominal pain or

discomfort, however the upper boundary of the confidence interval suggested worsening

symptoms of global relief or abdominal pain. The certainty in evidence for this outcome was rated

as low due to serious inconsistency and imprecision. Two studies compared changes in IBS-specific

QOL between the SSRI and placebo groups.66, 70 One study found a significantly greater

improvement in food avoidance score70 and the other study did not detect any differences.66 The

other critical or important outcomes could not be assessed based on the available data. There were

no long-term, data with SSRIs in IBS or depression to assess adverse events leading to treatment

withdrawal.

Discussion

SSRIs did not significantly improve global symptoms or abdominal pain in IBS although the overall

certainty in evidence is low. The ACG IBS Task Force rated the quality of evidence that SSRIs

improve overall symptoms in IBS as low.26 This meta-analysis differed from ours because their

assessment was based on pooling studies that reported either a global assessment of IBS

symptoms, improvement in abdominal pain or discomfort, or overall disease-specific QOL. Multiple

factors, including those arising from central and peripheral processes, contribute to the severity of

IBS symptoms. In some patients, SSRIs may improve the perception of overall IBS symptoms and

well-being by improving GI symptoms, coexistent alterations in mood and extraintestinal

symptoms.71 It is possible that serotonin-norepinephrine reuptake inhibitors (SNRIs) may have a

greater effect on abdominal pain in IBS due to their effects on both serotonin and norepinephrine

reuptake. SNRIs have been shown to be efficacious in other pain conditions but clinical trials in IBS

are lacking.62

Antispasmodics for IBS

Antispasmodics are commonly used in clinical practice to reduce abdominal pain associated with

IBS. Though a pharmacologically diverse class, anti-spasmodics are thought to relieve IBS

21

symptoms by reducing smooth muscle contraction and possibly visceral hypersensitivity.72 Of the

antispasmodics studied, only hyoscine, dicyclomine, and peppermint oil are available in the United

States.

Summary of evidence

This was based on a Cochrane Review that included 22 RCTs evaluating 1,983 IBS patients

(antispasmodics 1008; placebo 1975).73 Twelve different antispasmodics were assessed. There

was considerable variation between the studies concerning diagnostic and inclusion criteria, dosing

schedule and study endpoints. Compared to placebo, there were a significantly greater proportion

of patients taking antispasmodics who had adequate global relief of IBS symptoms (RR of 0.67; 95%

CI 0.55 to 0.80). The overall certainty in evidence, however, was low due to the serious risk of bias

and publication bias. Likewise, compared to placebo, anti-spasmodics showed improvement in

abdominal pain with a RR 0.74 (95% CI 0.59 to 0.93. For this outcome, the certainty in evidence

was very low due to risk of bias, publication bias, and imprecision (the upper boundary of the CI did

not cross our minimal clinically important threshold). The effect of individual antispasmodics was

difficult to interpret due to the small number of studies evaluated for each of the drugs. The most

common adverse events reported were dry mouth, dizziness, and blurred vision, but no serious

adverse events reported. We did not include adverse events leading to discontinuation due to the

lack consistent reporting.

Discussion

Antispasmodics include a wide array of pharmacological therapies that been used clinically for

many years but have not been subjected to rigorous large multicenter trials. There was

considerable variation among the trials and the quality of the studies was generally low. However,

antispasmodics were significantly associated with a greater relief of global symptoms and

abdominal pain, although the latter did not meet our criteria for being clinically meaningful. A

Cochrane Review73 found a beneficial effect for antispasmodics over placebo for improvement in

abdominal pain and global assessment. More recently, the ACG IBS Task Force recently rated the

quality of evidence for antispasmodics in the treatment of overall symptom improvement in IBS as

very low.26 It is not clear if antispasmodics are more efficacious in specific IBS subtypes but its

regular use in constipation may be limited due to its anticholinergic effects. While these

medications are often recommended for treatment of post-prandial symptoms in IBS, this has not

been specifically studied in RCTs.

EVIDENCE GAPS

22

Since the 2014 technical review, the Rome IV diagnostic criteria for IBS was published in 2016.32

The Rome IV criteria differ from the Rome III criteria25 in that abdominal discomfort has been

deleted from the definition and abdominal pain now is required to be present at least 1 day per

week on average during the preceding 3 months.32 Based on these changes fewer individuals meet

the Rome IV criteria for IBS compared to the Rome III criteria.74 However, for the purpose of RCTs

in IBS, which generally measure changes in abdominal pain, the Rome IV criteria are more

applicable. Nonetheless, it is not known whether these changes to the IBS diagnostic criteria would

alter the efficacy and safety of IBS treatments in RCTs.

Responder definitions have varied in multicenter IBS RCTs until the establishment of FDA

composite primary endpoints for IBS-C and IBS-D in 2012,34 which now allows greater

standardization of the efficacy of IBS treatments than in the past. However, these endpoints were

meant to serve as interim primary endpoints while a patient reported outcome (PRO) instrument

was being developed as recommended by the FDA guidance for PROs.75 Efforts to create a FDA

approved IBS PRO are ongoing but have not been completed. The FDA recommended enrollment

criteria and interim primary endpoints for IBS-C and IBS-D but not IBS-M. There continues to be a

lack of studies focusing on IBS-M and no consensus on the optimal primary endpoint for this bowel

habit subgroup. With respect to therapeutic agents that target abdominal pain relief without

significant effects on bowel habits, there is no established consensus on the inclusion and exclusion

criteria regarding bowel symptoms and treatment that normalizes bowel habits without an effect

on abdominal pain (e.g. anti-diarrheals, laxatives).

As stated in the 2014 technical review, a continued unmet need in IBS clinical trials is the lack of a

biomarker that can embody the different pathophysiologic mechanisms of IBS or that can reliably

predict treatment response to medications that have different predominant mechanisms of action

(e.g., normalizing bowel habits, visceral analgesic). However, a recent retrospective analysis of

almost 600 women with IBS-C undergoing a 12-week RCT with renzapride found that baseline

variation in abdominal pain, maximum baseline pain severity, and placebo response in study week

2 or 3 were associated with a response to placebo. Factors associated with a lack of response to

placebo were number of baseline CSBMs and final baseline pain ratings.76

Lastly, our current and previous technical reviews did not include non-pharmacologic interventions

which were beyond the scope of this review. Dietary modification, behavioral treatments, and

probiotics have shown beneficial effects in IBS patients and should be considered on an individual

basis.

23

CONCLUSION

In this updated technical review of pharmacologic treatment for IBS, we evaluated the efficacy and

safety of linaclotide and plecanatide in IBS-C and eluxadoline and retreatment with rifaximin in IBS-

D. We incorporated recent data from a multicenter, RCT conducted predominantly in China

evaluating the efficacy of linaclotide vs. placebo.23 We evaluated the effect of treatment on global

assessments, which were considered critical outcomes as well as individual symptom responses,

HRQOL and adverse events leading to treatment withdrawal, which were considered important

outcomes. The quality of evidence across all critical outcomes for linaclotide was high and was

moderate for plecanatide, eluxadoline and retreatment with rifaximin. In addition, this technical

review summarized the key findings from the 2014 technical review that evaluated the efficacy and

safety of lubiprostone and PEG laxatives in IBS-C, single course of rifaximin, alosetron, and

loperamide in IBS-D and TCAs, SSRIs and antispasmodics in IBS.12 Using the GRADE process in both

technical reviews allowed us to rate the quality of evidence and provide greater transparency and

explicitness about the comparators used and outcomes measured. To weigh the trade-offs involved

with different interventions, the GRADE process presents the absolute risk differences for both

beneficial outcomes and harms. This technical review provided evidence of IBS treatment efficacy

and harm in a structured manner and was used to inform the accompanying IBS Guideline Update.

25

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