cadth rapid response report: summary with ......listed for the treatment of chronic constipation,...

Service Line: Rapid Response Service

Version: 1.0

Publication Date: December 6, 2017

Report Length: 21 Pages

CADTH RAPID RESPONSE REPORT:

SUMMARY WITH CRITICAL APPRAISAL

Prucalopride for Gastrointestinal Motility Disorders: A Review of Clinical Effectiveness

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 2

Authors: Chuong Ho, Melissa Severn

Cite As: Prucalopride f or Gastrointestinal Motility Disorders: Clinical Ef f ectiveness . Ottawa: CADTH; Dec 2017. (CADTH rapid response report: summary with

critical appraisal).

ISSN: 1922-8147 (online)

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Context and Policy Issues

Gastrointestinal motility disorders include a variety of pathological conditions involving the

motility of the gastrointestinal tract such as chronic constipation, ileus, refractory

gastroparesis, and intestinal pseudo-obstruction. The estimated global prevalence of

chronic idiopathic constipation in adults is 14%,1,2

and one in four Canadians has symptoms

of constipation.3 Post-operative ileus, a hypomotility condition of the gastrointestinal tract

leading to accumulation of gas and fluid in the bowel following gastrointestinal surgeries, is

the second most common reason for hospital readmission following surgery in the United

States.4,5

Chronic idiopathic intestinal pseudo-obstruction is a rare condition with a wide

spectrum of severity, and denotes a clinical syndrome of apparent bowel obstruction in the

absence of an obstructing lesion.6-9

Gastroparesis, a syndrome characterized by delayed

gastric emptying, can occur in 9.6 women and 37.8 men per 100,000 persons in the Unites

States.10

Gastrointestinal motility disorders such as chronic constipation can be treated by lifestyle

modification, laxative therapy, and a variety of pharmacological classes, such as 5-

hydroxytryptamine 4 receptor agonists (5-HT4 agonists e.g., prucalopride, tegaserod,

velusetrag, naronapride), diphenylmethanes or derivatives (bisacodyl and sodium

picosulphate), guanylate cyclase C receptor agonist (linaclotide), chloride channel type 2

opener (lubiprostone) and apical sodium bile acid inhibitor (elobixibat).11-13

Prucalopride, a

highly selective 5-HT4 agonist drug that stimulates peristalsis and increases colonic

motility, has been used for the treatment of chronic constipation,14

ileus,15

intestinal pseudo-

obstruction,16

and gastroparesis.17

In 2012, the Canadian Drug Expert Committee (CDEC) recommended prucalopride not be

listed for the treatment of chronic constipation, citing unclear clinical effectiveness in the

population of interest (patients who had previously failed laxative therapy).18

This Rapid

Response report aims to review the clinical effectiveness of prucalopride for chronic

constipation, ileus, refractory gastroparesis, and intestinal pseudo-obstruction compared to

other medications and placebo.

Research Question

What is the clinical effectiveness of prucalopride for the treatment of gastrointestinal motility

disorders (i.e., chronic constipation, ileus, refractory gastroparesis, intestinal pseudo-

obstruction)?

Key Findings

Findings from three SRs showed that prucalopride seems to be a beneficial

pharmacotherapy in the treatment of chronic constipation, but with an increase in adverse

event rates compared to placebo. Indirect comparison showed there was no significant

difference in efficacy among prucalopride and other pharmacotherapies. Limited evidence

from two RCTs found prucalopride is a safe and effective treatment to reduce the

symptoms of post-operative ileus and chronic intestinal pseudo-obstruction. There was no

evidence found on the comparative efficacy of prucalopride for refractory gastroparesis.


Methods

A limited literature search was conducted on key resources including PubMed, Embase,

The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD)

databases, Canadian and major international health technology agencies, as well as a

focused Internet search. No filters were applied to limit the retrieval by study type.

Conference abstracts were removed from the search results. The search was also limited to

English language documents published between Jan 1, 2012 and Nov 8, 2017.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles

and abstracts were reviewed and potentially relevant articles were retrieved and assessed

for inclusion. The final selection of full-text articles was based on the inclusion criteria

presented in Table 1.

Table 1: Selection Criteria

Population Adults and children who require treatment for gastrointestinal motility disorders (i.e., chronic constipation, ileus, refractory gastroparesis, intestinal pseudo-obstruction)

Intervention Prucalopride (Resotran)

Comparator Other medications, placebo

Outcomes Clinical effectiveness, clinical benefit, safety

Study Designs Heath technology assessments, systematic reviews (SRs), meta-analyses, randomized controlled trials (RCTs), non-RCTs

RCT = randomized controlled trial.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they

were duplicate publications were already reported in the included SRs, or were published

prior to 2012.

Critical Appraisal of Individual Studies

The included systematic reviews and clinical studies were assessed using the AMSTAR,19

and Downs and Black20

checklists, respectively. Summary scores were not calculated for

the included studies; rather, a review of the strengths and limitations of each included study

were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 343 citations were identified in the literature search. Following screening of titles

and abstracts, 334 citations were excluded and nine potentially relevant reports from the

electronic search were retrieved for full-text review. No potentially relevant publication was

retrieved from the grey literature search. Of these potentially relevant articles, four

publications were excluded for various reasons, while five publications (three SRs and two


primary clinical studies) met the inclusion criteria and were included in this report. Appendix

1 describes the PRISMA flowchart of the study selection.

Summary of Study Characteristics

The literature search identified five relevant studies, three SRs21-23

and two clinical

trials.24,25

One SR performed meta-analysis on 13 phase II and III RCTs that reported the

efficacy of selective 5-HT4 agonists drugs for chronic constipation including prucalopride 1

to 4mg/day (duration of prucalopride use maximum 12 weeks) compared to placebo (12

trials) and laxative (one trial). Outcomes reported were 3 or more complete spontaneous

bowel movements (CSBM) per week and increase over baseline by 1 or more CSBM per

week, quality of life, and adverse events . The meta-analysis was performed in the US. A

second SR performed meta-analysis on 16 phase II and phase III randomized placebo-

controlled trials that reported the efficacy of prucalopride1 to 4mg/day in patients with

chronic constipation (duration of prucalopride use ranged from 1-12 weeks).22

Outcomes

reported were frequency of spontaneous bowel movements (SBM) per week and adverse

events. The SR was performed in UK. A third SR performed meta-analysis on 21 phase IIB

and phase III RCTs that reported the efficacy of current drugs for chronic constipation

including prucalopride 1 to 4 mg/day (duration of prucalopride use ≥4 weeks), and

compared to placebo.23

Network meta-analyses were used to compare different drugs, and

comparison to placebo was direct head-to-head comparison. Outcomes reported were 3 or

more CSBM per week and increase over baseline by 1 or more CSBM per week, change

from baseline in the number of SBM per week and change from baseline in the number of

CSBM per week. The meta-analysis was performed in the US. In all three SRs, it is unclear

whether the patient population was comprised totally of patients in whom laxatives failed to

provide adequate relief or whether it was a mixed population.

One primary clinical study was a phase II double blind RCT that evaluates the efficacy of

prucalopride 2mg/day for the treatment of post-operative ileus in 110 patients.24

Outcomes

reported were time to defecation, time to first passage of flatus, post-operative length of

stay, surgical complications, and inflammatory parameters. The RCT was conducted in

China. The second clinical trial is a randomized, double-blind, placebo-controlled cross-over

trial that evaluates the effect and safety of prucalopride 2 to 3mg/day on seven patients with

chronic intestinal pseudo-obstruction.25

Outcomes reported were symptoms using diary

recording (pain, vomiting, nausea, bloating), rescue analgesia use, body weight, and

adverse events. The trial was conducted in UK, Belgium and Australia.

Characteristics of the included studies are detailed in Appendix 2.

Summary of Critical Appraisal

One included SR21

described an a priori design, had independent study selection and data

extraction procedures, performed by two reviewers, in place, conducted a comprehensive

literature search, provided a list of included studies and study characteristics, and stated

potential conflict of interests for the authors of the review. Study quality of the included

studies was provided and used in formulating conclusions. The review did not assess

publication bias, and a list of excluded studies was not provided;

The second included SR22

described an a priori design, had independent study selection

and data extraction procedures, performed by two reviewers, in place, conducted a

comprehensive literature search, provided a list of included studies and study

characteristics, and stated potential conflicts of interest for the authors of the review.


Overall study quality was assessed and used in formulating conclusions based on the

GRADE framework but quality of individual studies was not reported. The review did not

assess publication bias, a list of excluded studies was not provided.

The third included SR23

provided an a priori design, had independent study selection and

data extraction procedures, performed by two reviewers, in place, conducted a

comprehensive literature search, and provided a list of included studies and study

characteristics. The quality of the included studies was provided and used in formulating

conclusions. Conflicts of interest were stated for the authors of the review. The review did

not assess publication bias, and a list of excluded studies was not provided. Comparison

between drugs was done using network meta-analyses from trials with heterogeneity.

In all three SRs, there was heterogeneity across trials in designs (phase II and III trials),

duration of intervention, and follow-up periods, which would caution the interpretation of the

reviews conclusion. It was unclear in the included SRs whether patient population was

purely comprised of those to whom laxative therapy had failed.

The included primary studies24,25

had clearly described hypotheses, method of selection

from source population and representation of the study population, main outcomes,

interventions, patient characteristics, and main findings. Randomization methods were

described and methods were adequate to maintain blinding. Loss to follow-up was reported.

Estimates of random variability and actual probability values were provided. One trial met

the required sample size based on a power calculation,24

and one trial’s population did not

have enough power to detect clinically important effect.25

Details of the critical appraisal of the included studies are presented in Appendix 3.

Summary of Findings

What is the clinical effectiveness of prucalopride for the treatment of gastrointestinal motility

disorders (i.e., chronic constipation, ileus, refractory gastroparesis, and intestinal pseudo-

obstruction)?

The first SR compared the clinical efficacy and safety of prucalopride and two other 5 -HT4

agonists drugs (velusetrag, naronapride) to controls (12 trials to placebo and one trial to

laxative) in patients with chronic constipation.21

All drugs evaluated (prucalopride,

velusetrag, naronapride) were superior to placebo in achieving ≥3 CSBM per week

(increasing by an average of two times the chance) All drugs evaluated were superior to

placebo in achieving increase over baseline >1 CSBM per week (increase by an average of

about 1.5 times the chance). There were no differences among all the evaluated drugs in all

efficacy outcomes. Patients treated with prucalopride experienced a clinically significant

improvement in quality of life compared to placebo (increase by an average of about 1.5

times the chance). There was no quality of life data on velusetrag and naronapride.

Prucalopride and velusetrag treatment lead to an increase in the risk of minor adverse

events of 1.2 to 1.3 times compared to placebo, with headache, nausea, abdominal pain or

cramps, and diarrhea being the most commonly reported adverse events . There were no

adverse events data for naronapride. The authors concluded that efficacy and safety of

highly selective 5-HT4 agonists were demonstrated for the treatment of chronic

constipation.

The second SR compared the clinical efficacy and safety of prucalopride 1 to 4mg/day to

placebo in patients with chronic constipation (duration of prucalopride use ranged from 1-12

weeks).22

Prucalopride at different dosages moderately increased the frequency of


spontaneous bowel movements per week as compared to placebo (standardized mean

difference >0.2%, ranging from 0.33% to 0.42%). Differences from placebo were

statistically significant. Prucalopride treatment lead to an increase in the risk of minor

adverse events, from 1.5 to 2 times compared to placebo, with headache, nausea,

abdominal pain or cramps, and diarrhea being the most commonly reported adverse

events. The authors concluded that prucalopride is a beneficial pharmacotherapy in

patients with chronic constipation.

The third SR compared the clinical efficacy of prucalopride1 to 4mg/day to placebo and

other drugs in patients with chronic constipation.23

All drugs evaluated (prucalopride,

velusetrag, tegaserod, bisacodyl, sodium picosulphate, linaclotide) were superior to placebo

in achieving ≥3 CSBM per week (increasing by an average of two times the chance). All

drugs evaluated (prucalopride, velusetrag, tegaserod, elobixibat, bisacodyl, sodium

picosulphate, linaclotide) were also superior to placebo in achieving increase over baseline

>1 CSBM per week (increase by an average of about 1.5 times the chance). Secondary

outcomes such as change from baseline in CSBM per week, and SBM per week were also

favourably affected by the evaluated drugs compared to placebo. There were no

differences among all the evaluated drugs in all efficacy outcomes. The authors concluded

that all evaluated drugs were superior to placebo in the treatment of chronic constipation,

and no drug was superior at achieving outcomes.

One RCT compared the efficacy of prucalopride to placebo for the treatment of post-

operative ileus in patients undergoing elective gastrointestinal surgery.24

Prucalopride

improved all outcomes such as time to defecation, passage of flatus, post-operative length

of stay, number of patients with prolonged ileus, and inflammatory marker C reactive

protein level compared to placebo. More patients in the prucalopride than control group had

diarrhea. All differences were statistically significant. There were no significant post-

operative complications such as infection or mortality between the groups. The authors

concluded that prucalopride is a safe and effective treatment to reduce post-operative ileus

and systemic inflammation without affecting post-operative complications in patients

undergoing elective gastrointestinal surgery.

The second RCT compared the efficacy of prucalopride to placebo on patients with chronic

intestinal pseudo-obstruction.25

Prucalopride improved symptoms of intestinal pseudo-

obstruction such as pain, nausea, vomiting and bloating, and reduced the use of rescue

analgesia compared to placebo. All differences were statistically significant. Body weight

was stable for all patients. There were no drug-related adverse events in the groups. The

authors concluded that prucalopride reduced symptoms for patients with chronic intestinal

pseudo-obstruction.

The main findings of the included studies are presented in Appendix 4.

Limitations

Findings from the included narrative SRs need to be interpreted with caution as there was

heterogeneity across trials in designs, patients’ eligibility criteria, duration of intervention,

and follow-up periods. Comparative analysis between prucalopride and other

pharmacotherapies were performed by indirect comparison. The SRs are not unique and

included a significant overlap of trials, though some reported different outcomes. One of

the included clinical trials did not have enough power to detect a clinically important effect.

There was no evidence found on the efficacy of prucalopride for refractory gastroparesis.


Conclusions and Implications for Decision or Policy Making

Findings from three SRs showed that prucalopride seems to be a beneficial

pharmacotherapy in the treatment of chronic constipation, but with an increase in adverse

event rates compared to placebo. Indirect comparison showed there was no significant

difference in efficacy among prucalopride and other pharmacotherapies. Limited evidence

from two RCTs found prucalopride is a safe and effective treatment to reduce the

symptoms of post-operative ileus and chronic intestinal pseudo-obstruction. There was no

evidence found on the comparative efficacy of prucalopride for refractory gastroparesis.

In 2012, the Canadian Drug Expert Committee (CDEC) recommended prucalopride not be

listed for the treatment of chronic constipation,18

with one of the reasons being uncertainty

in the clinical and cost-effectiveness in relevant population, because trials included a

proportion of patients who had not previously failed laxative therapy.

The 2016 SR that compared the clinical efficacy and safety of prucalopride to placebo in

patients with chronic constipation, and that was included in this report22

did not specifically

mention in the description of trial selection criteria that trials had to include patients who had

failed laxative therapy, but the conclusion and the discussion seemed to indicate that its

findings are on a population that was laxative-resistant. The authors mentioned that

“Prucalopride is clinically a beneficial pharmacotherapy for chronic constipation and its

routine use may be considered in patients with chronic simple laxative-resistant

constipation” (p 412) and further “The findings of the current study are pertinent to only that

group of patients which have failed basic laxative therapy (lactulose, ispaghula husk, and

senna), life style modifications and stronger laxatives therapy (macrogol, b isacodyl or

glycerol suppository, sodium phosphate, and arachis oil enema), and therefore, conclusion

cannot be generalized to all types of constipation and on group of patients where early

treatment is not optimally tested” (p 419). In summary, despite the evidence from the

included SRs suggesting a benefit of prucalopride in patients who failed prior laxative

therapy, the proportion of patients who met that criteria in the included trials is unclear.

Direct comparisons between prucalopride and other pharmacotherapies, and cost-

effectiveness studies on prucalopride treatment on patients who have failed laxative

therapy are needed to further assess the benefits of prucalopride use for chronic

constipation, ileus, refractory gastroparesis and intestinal pseudo-obstruction.


References

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7. Knowles CH, Silk DB, Darzi A, Veress B, Feakins R, Raimundo AH, et al. Deranged smooth muscle alpha-actin as a biomarker of intestinal pseudo-obstruction: a controlled multinational case series. Gut [Internet]. 2004 Nov [cited 2017 Nov 16];53(11):1583-9.

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13. Davis M, Gamier P. New options in constipation management. Curr Oncol Rep. 2015 Dec;17(12):55.

14. Shin A. Patient considerations in the management of chronic constipation: focus on prucalopride. Patient Prefer Adherence [Internet]. 2016 [cited 2017 Nov 9];10:1373-84.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970632

15. Smart CJ, Malik KI. Prucalopride for the treatment of i leus. Expert Opin Invest Drugs. 2017 Apr;26(4):489-93.

16. Oustamanolakis P, Tack J. Prucalopride for chronic intestinal pseudo-obstruction. Aliment Pharmacol Ther. 2012 Feb;35(3):398-9.

17. Langworthy J, Parkman HP, Schey R. Emerging strategies for the treatment of gastroparesis. Expert Review of Gastroenterology and Hepatology. 2016;10(7):817-25.

18. Prucalopride (Resotran - Janssen Inc.) Indication: constipation, chronic [Internet]. Ottawa: CADTH; 2012 Jun 20. [cited 2017 Nov 16]. Available from:

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19. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a criti cal appraisal tool for systematic reviews that include randomised or non-randomised studies

of healthcare interventions, or both. BMJ [Internet]. 2017;358:j4008. Available from:

http://www.bmj.com/content/bmj/358/bmj.j4008.full.pdf

20. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun;52(6):377-84. Available

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21. Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH. Systematic review with meta-

analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53.

22. Sajid MS, Hebbar M, Baig MK, Li A, Philipose Z. Use of prucalopride for chronic constipation: a systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil [Internet]. 2016 Jul 30;22(3):412-22. Available from:


23. Nelson AD, Camilleri M, Chirapongsathorn S, Vijayvargiya P, Valentin N, Shin A, et al. Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a

systematic review and network meta-analysis. Gut. 2017 Sep;66(9):1611-22.

24. Gong J, Xie Z, Zhang T, Gu L, Yao W, Guo Z, et al. Randomised clinical trial:

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Appendix 1: Selection of Included Studies

334 citations excluded

9 potentially relevant articles retrieved for scrutiny (full text, if available)

0 potentially relevant reports retrieved from other sources (grey

literature, hand search)

9 potentially relevant reports

4 reports excluded: - already reported in included SRs (3)

- reviews (1)

5 reports included in review

343 citations identified from electronic

literature search and screened


Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Systematic Reviews

First Author, Year,

Country

Objectives

Literature Search Strategy

Inclusion Criteria Exclusion Criteria

Studies included

Main outcomes

Shin,21

2014, US “To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or

naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC” (p 239)

We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase,

Cochrane Library, and Web of Science/Scopus for randomised, controlled trials

of highly selective 5-HT4 agonists in adults with CC, with no minimum

duration of therapy (maximum 12 weeks) or date limitations (p 239).

“This review was limited to RCTs studying the effects of any HS 5-HT4 receptor agonist including, but not limited to, prucalopride, velusetrag and naronapride in

adults with CC” (p 240)

Duration of therapy (maximum 12 weeks)

Trials not satisfying inclusion criteria

13 RCTs

11 prucalopride

1 velusetrag

1naronapride

Efficacy:

≥3 CSBM per week

Increase over baseline by ≥1 CSBM per week

Quality of life:

PAC-QOL (PAC-QOL questionnaire)

PAC-SYM (PAC-SYM questionnaire)

Improvement

of at least one point on the overall score was chosen as

a clinically significant improvement)

Adverse events

Sajid,22

2016, UK “This article highlights the role of prucalopride in the management of chronic constipation based upon the principles of meta-analysis using data reported in the published randomized, controlled trials” (p 412)

“Electronic medical databases such as the Medline, EMBASE,

Cochrane Colorectal Cancer Group Controlled Trial Register, Pain...and the Cochrane Central Register of Controlled Trials (CENTRAL) in the

Phase II and phase III randomised,

placebo-controlled trials (RCT) reported the effectiveness of prucalopride in patients with chronic constipation (duration of prucalopride use ranged from 1-12 weeks)

Trials not satisfying inclusion criteria

16 RCTs (3943 patients)

Efficacy:

Frequency of SBM per week

Adverse events


First Author, Year,

Country

Objectives

Literature Search Strategy

Inclusion Criteria Exclusion Criteria

Studies included

Main outcomes

Cochrane Library along with the Science Citation Index Expanded were explored until May 2015 to find published randomized, controlled trials” (p 413)

Nelson,23

2017, US

“To compare efficacy of pharmacotherapies

for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis” (p1611)

“We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane

Central, as well as original data from authors or drug

companies for the medications used for CIC” (p 1611)

Phase IIB and phase III randomised,

placebo-controlled trials (RCT) of ≥4 weeks’ treatment

for CIC in adults with functional

constipation

Trials not satis fied inclusion criteria

21 RCTs (9189 patients)

9 prucalopride

3 lubiprostone

3 linaclotide

2 tegaserod

1 velusetrag

1 elobixibat

1 bisacodyl

1 sodium picosulphate (NaP)

Primary outcomes:

≥3 CSBM per week

Increase over baseline by ≥1 CSBM per week

Secondary outcomes: change from baseline in the number of SBM per week and change from baseline in CSBM per week.

CC = chronic constipation; CSBM = complete spontaneous bowel mov ements; PAC-QOL = Patient Assessment of Constipation Quality of lif e; PAC-SYM = Patient

Assessment of Constipation Sy mptoms; SBM = spontaneous bowel mov ements


Table 3: Characteristics of Included Clinical Studies

First Author, Year, Country

Study Design Study Objectives

Interventions/Comparators

Patients Main Outcomes

Gong,24

2016, China

Phase II double-blind RCT “To evaluate the effect and safety of prucalopride on post-operative ileus and surgical outcomes after elective gastrointestinal surgery” (p 778)

Prucalopride 2 mg/day Placebo

110 patients undergoing elective gastrointestinal surgery (mean age 37 for prucalopride, 38 for placebo)

Primary outcome: Time to defecation Secondary outcomes: Time to first passage of flatus Post-operative length of stay Surgical complications Inflammatory parameters Adverse events

Emmanuel,25

2012, UK, Belgium, Australia

Randomized, double-blind, placebo-controlled cross-over trial To evaluate the effect and safety of prucalopride on chronic intestinal pseudo-obstruction

Prucalopride2- 3mg/day Placebo

7 patients with chronic idiopathic chronic intestinal pseudo-obstruction (mean age 42 years) Patients were treated for periods of12 weeks with either placebo or prucalopride once daily. Patients were assigned in consecutive order and the following four sequences were used: ABAB, BABA, ABBA and BAAB (A = placebo, B = prucalopride).

Efficacy: Symptoms using diary recording (pain, vomiting, nausea, bloating) Rescue analgesia use Body weight Adverse events

RCT = randomized controlled trial


Appendix 3: Critical Appraisal of Included Publications

Table 4: Summary of Critical Appraisal of Included Studies

First Author,

Publication Year

Strengths Limitations

Critical appraisal of included systematic review (AMSTAR 219

)

Shin21

a priori design provided independent studies selection and data

extraction procedure in place

comprehensive literature search performed list of included studies, studies

characteristics provided

quality assessment of included studies

provided and used in formulating

conclusions

conflict of interest stated

assessment of publication bias not performed

list of excluded studies not provided

heterogeneity across trials in study design

(phase II and III), duration of intervention, and

follow-up periods

Sajid22

a priori design provided independent studies selection and data

extraction procedure in place

comprehensive literature search performed list of included studies, studies

characteristics provided


performed and used in formulating

conclusions






follow-up periods

Nelson23

a priori design provided

independent studies selection and data extraction procedure in place

comprehensive literature search performed

list of included studies, studies characteristics provided


provided and used in formulating

conclusions






follow-up periods

Critical appraisal of included clinical trial (Downs and Black20

)

Gong24

randomized controlled trial

both the investigator and the patient were blinded to the treatment assignment.

hypothesis clearly described

method of selection from source population and representation described

loss to follow-up reported

main outcomes, interventions, patient characteristics, and main findings clearly described

estimates of random variability and actual probability values provided

study had sufficient power to detect a

single-centre study with relatively small sample size


First Author,

Publication Year

Strengths Limitations

clinically important effect

Emmanuel25

randomized controlled trial

both the investigator and the patient wereblinded to the treatment assignment.

hypothesis clearly described

method of selection from source population and representation described

loss to follow-up reported

main outcomes, interventions, patient characteristics, and main findings clearly described

estimates of random variability and actual probability values provided

single-centre study with insufficient power to detect a clinically important effect


Appendix 4: Main Study Findings and Author’s Conclusions

Table 5: Main Study Findings and Authors’ Conclusions

Main Study Findings Authors’ Conclusions

Shin21

(Systematic Review)

≥3 CSBM/week All drugs were superior to placebo Prucalopride RR 1.63; 95% CI 1.07-2.49 (data from 9 trials) Velusetrag RR 4.44; 95% CI 1.83-10.75 (data from 1 trial) Naronapride RR 4.49; 95% CI 1.13-17.86 (data from 1 trial) Overall: RR 1.85; 95% CI 1.23-2.79 Increase over baseline by ≥1 CSBM/week All drugs were superior to placebo Prucalopride RR 1.58; 95% CI 1.18-2.12 (data from 9 trials) Velusetrag RR 2.80; 95% CI 1.64-4.77 (data from 1 trial) Naronapride RR 0.94; 95% CI 0.73-1.21 (data from 1 trial) Overall: RR 1.57; 95% CI 1.19-2.06 Risk of achieving improvement in PAC-QOL satisfaction score ≥1 Prucalopride RR 1.51; 95% CI 1.07-2.11 (data from 6 trials) No data for other drugs Risk of achieving improvement in PAC-SYM score ≥1 Prucalopride RR 1.47; 95% CI 1.10-1.98 (data from 6 trials) No data for other drugs Adverse events Prucalopride RR 1.24; 95% CI 1.12-1.38 (data from 11 trials) Velusetrag RR 1.35; 95% CI 1.03-1.78 (data from 1 trial)

“Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4 agonists in the treatment of chronic constipation” (p 239).


Main Study Findings Authors’ Conclusions No data for naronapride Overall: RR 1.25; 95% CI 1.14-1.38

Sajid22

(Systematic Review)

Frequency of spontaneous bowel movements per week vs placebo : Prucalopride1 mg SMD 0.42 (95% CI, 0.18-0.66); P = 0.006 (data from 5 trials) Prucalopride 2 mg SMD 0.34 (95% CI, 0.11-0.56); P = 0.003 (data from 9 trials) Prucalopride 4 mg SMD 0.33 (95% CI, 0.22-0.44); P = 0.00001 (data from 5 trials) Adverse events vs placebo: The most commonly reported adverse events : headache, nausea, abdominal pain or cramps, and diarrhea Prucalopride 1 mg OR 2.02; 95% CI, 1.10-3.72; P = 0.020 (data from 7 trials) Prucalopride 2 mg OR 1.76; 95% CI, 1.33-2.34; P< 0.0001(data from 13 trials) Prucalopride 4 mg OR 1.52; 95% CI, 1.13-2.05; P = 0.006 (data from 7 trials)

“Prucalopride is clinically a beneficial pharmacotherapy for chronic constipation and its routine use may be considered in patients

with chronic simple laxative-

resistant constipation” (p 412) “The findings of the current study are pertinent to only that group of patients which have failed basic laxative therapy (lactulose, ispaghula husk, and senna), life style modifications and stronger laxatives therapy (macrogol, b isacodyl or glycerol suppository, sodium phosphate, and arachis oil enema), and therefore, conclusion cannot be generalized to all types of constipation and on group of patients where early treatment is not optimally tested” (p 419)

Nelson23

(Systematic Review)

≥3 CSBM/week All drugs were superior to placebo Prucalopride RR 1.85; 95% CI 1.35-2.54 (data from 9 trials) Velusetrag RR 4.86; 95% CI 2.02-11.71 (data from 1 trial) Tegaserod RR 1.47; 95% CI 1.13-1.92 (data from 1 trial) Bisacodyl RR 2.46; 95% CI 1.81-3.35 (data from 1 trial) Sodium picosulphate (NaP) RR 2.83; 95% CI 1.93-4.16 (data from 1 trial) Linaclotide RR 1.96; 95% CI 1.12-3.44 (data from 1 trial) Overall: RR 2.00; 95% CI 1.59-2.52

“Our study has shown that each drug used in the treatment of CIC is superior to placebo, based on the published randomised, placebo-controlled trials” (p 1617) “No drug was superior at improving the primary end points on network meta-analysis” (p 1611)


Main Study Findings Authors’ Conclusions Increase over baseline by ≥1 CSBM/week All drugs were superior to placebo Prucalopride RR 1.54; 95% CI 1.28-1.86 (data from 8 trials) Velusetrag RR 3.10; 95% CI 1.83-5.24 (data from 1 trial) Tegaserod RR 1.32; 95% CI 1.14-1.52 (data from 2 trials) Elobixibat RR 1.97; 95% CI 1.26-3.07 (data from 1 trial) Bisacodyl RR 2.04; 95% CI 1.62-2.57 (data from 1 trial) Sodium picosulphate (NaP) RR 2.03; 95% CI 1.56-2.64 (data from 1 trial) Linaclotide RR 1.72; 95% CI 1.18-2.52 (data from 1 trial) Overall: RR 1.65; 95% CI 1.44-1.88 Change in CSBM/week from baseline All drugs were superior to placebo Prucalopride WMD 0.90; 95% CI 0.70-1.10 (data from 4 trials) Elobixibat WMD 1.99; 95% CI 0.95-3.04 (data from 1 trial) Bisacodyl WMD 3.20; 95% CI 2.66-3.74 (data from 1 trial) Sodium picosulphate (NaP) WMD 2.00; 95% CI 1.51-2.49 (data from 1 trial) Linaclotide WMD 1.57; 95% CI 1.11-2.04 (data from 3 trials) Overall: WMD 1.32; 95% CI 1.16-1.48 Change in SBM/week from baseline All drugs were superior to placebo Prucalopride WMD 2.03; 95% CI 1.73-1.10 (data from 4 trials)


Main Study Findings Authors’ Conclusions Lubiprostone WMD 1.91; 95% CI 1.41-2.41 (data from 3 trials) Elobixibat WMD 2.08; 95% CI0.92-3.24 (data from 1 trial) Bisacodyl WMD 4.90; 95% CI4.14-5.66 (data from 1 trial) Sodium picosulphate (NaP) WMD 3.20; 95% CI 2.55-3.85 (data from 1 trial) Linaclotide WMD 2.11; 95% CI 1.68-2.54 (data from 3 trials) Overall: WMD 2.31; 95% CI 2.12-2.50

Gong24

(Clinical Trial)

Time to defecation Prucalopride 65.0 h Placebo 94.5 h, P = 0.001 Passage of flatus Prucalopride 53.0 h Placebo 73.0 h, P5 days) Prucalopride 16.4% Placebo 34.5%, P = 0.026 C-reactive protein level on post-operative day 5 Prucalopride 35.67 mg/L Placebo 59.07 mg/L, P = 0.040 Post-operative complications No significant difference between the groups(P = 0.606) Adverse events AEs reported by 52 of the 110 (47.3%) patients, and the total number of patients with at least one AE was comparable between the groups (P = 0.445) More patients in the prucalopride than control group had diarrhoea (P = 0.039),

“Prucalopride is a safe and effective treatment to reduce post-operative ileus and systemic inflammation without affecting post-operative complications in patients undergoing elective gastrointestinal surgery” (p 778)

Emmanuel25

(Clinical Trial)

7 patients participated (3 discontinued, 2 due to study length, and 1 on prucalopride due to unrelated malnutrition and bronchopneumonia) 4 patients completed the study Symptoms Pain: prucalopride statistically significantly improved pain in 2/4 patients (P< 0.05) Nausea: prucalopride statistically significantly reduced nausea in 1/4 patients (P< 0.05) Vomiting: prucalopride statistically significantly reduced vomiting in 2/4 patients (P< 0.05)

“Prucalopride relieves symptoms in selected patients with chronic pseudo-obstruction” (p 48)


Main Study Findings Authors’ Conclusions Bloating: prucalopride statistically significantly reduced bloating in 2/4 patients (P< 0.05) Rescue analgesia use 2/4 patients used on-demand (rescue) analgesia during the study. For both patients , the number of analgesia intakes decreased substantially during treatment with prucalopride compared with the placebo periods (P< 0.001) Body weight: was stable for all 4 patients Adverse events 3/4 patients reported adverse events. Most common complaints were of abdominal pain, constipation and vomiting; none were judged by the investigator to be drug related.

95% CI = 95% conf idence interv al; OR = odds ratio; CSBM = complete spontaneous bowel mov ements; RR = relativ e risk; SBM = spontaneous bowel mov ements; SMD

= standardized mean dif f erence; WMD = weighted mean dif f erence

cadth rapid response report: summary with ......listed for the treatment of chronic constipation,...

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