Prucalopride for Gastrointestinal Motility Disorders: a Review of Clinical Effectiveness

Home , Macrogol, Prucalopride, Tegaserod

CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL Prucalopride for Gastrointestinal Motility Disorders: A Review of Clinical Effectiveness

Service Line: Rapid Response Service Version: 1.0 Publication Date: December 6, 2017 Report Length: 21 Pages

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)

Disclaimer: The inf ormation in this document is intended to help Canadian health care decision-makers, health care prof essionals, health sy stems leaders, and policy -makers make well-inf ormed decisions and thereby improv e the quality of health care serv ices. While patients and others may access this document, the document is made av ailable f or inf ormational purposes only and no representations or warranties are made with respect to its f itness f or any particular purpose. The inf ormation in this document should not be used as a substitute f or prof essional medical adv ice or as a substitute f or the application of clinical judgment in respect of the care of a particular patient or other prof essional judgment in any decision-making process. The Canadian Agency f or Drugs and Technologies in Health (CADTH) does not endorse any inf ormation, drugs, therapies, treatments, products, processes, or serv ic es.

While care has been taken to ensure that the inf ormation prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was f irst published by CADTH, CADTH does not make any guarantees to that ef f ect. CADTH does not guarantee and is not responsible f or the quality , currency , propriety , accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The v iews and opinions of third parties published in this document do not necessarily state or ref lect those of CADTH.

CADTH is not responsible f or any errors, omissions, injury , loss, or damage arising f rom or relating to the use (or misuse) of any inf ormation, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not hav e control ov er the content of such sites. Use of third-party sites is gov erned by the third-party website owners’ own terms and conditions set out f or such sites. CADTH does not make any guarantee with respect to any inf ormation contained on such third-party sites and CADTH is not responsible f or any injury , loss, or damage suf f ered as a result of using such third-party sites. CADTH has no responsibility f or the collection, use, and disclosure of personal inf ormation by third-party sites.

Subject to the af orementioned limitations, the v iews expressed herein are those of CADTH and do not necessarily represent the v iews of Canada’s f ederal, prov incial, or territorial gov ernmentsor any third party supplier of inf ormation.

This document is prepared and intended f or use in the context of the Canadian health care sy stem. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising f rom or relating to the content or use (or misuse) of this document will be gov erned by and interpreted in accordance with the laws of the Prov ince of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusiv e jurisdiction of the courts of the Prov ince of Ontario, Canada.

The copy right and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document f or non-commercial purposes only , prov ided it is not modif ied when reproduced and appropriate credit is giv en to CADTH and its licensors.

About CADTH: CADTH is an independent, not-f or-prof it organization responsible f or prov iding Canada’s health care decision-makers with objectiv e ev idence to help make inf ormed decisions about the optimal use of drugs, medical dev ices, diagnostics, and procedures in our health care sy stem.

Funding: CADTH receiv es f unding f rom Canada’s f ederal, prov incial, and territorial gov ernments, with the exception of Quebec.

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 2

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.

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 3

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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 4

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 SRs 21-23 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.

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 5

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

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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 6

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.25Prucalopride 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.

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 7

Conclusions and Implications for Decision or Policy Making

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, bisacodyl 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.

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 8

References 1. Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol. 2011 Sep;106(9):1582-91. 2. Digestive diseases statistics for the United States [Internet]. Bethesda (MD): National Institute of Diabetes and Dgestive and Kidney Diseases; 2014 Nov. [cited 2017 Nov 20]. Available from: https://www.niddk.nih.gov/health-information/health- statistics/digestive-diseases 3. Understanding the prevalence and impact of constipation in Canada [Internet]. Oakville (ON): Canadian Digestive Health Foundation; 2014 Feb. [cited 2017 Nov 16]. Available from: http://www.cdhf.ca/bank/document_en/76understanding-the-prevalence-and- impact-of-constipation-in-canada.pdf 4. Merkow RP, Ju MH, Chung JW, Hall BL, Cohen ME, Williams MV, et al. Underlying reasons associated with hospital readmission following surgery in the United States. JAMA. 2015 Feb 3;313(5):483-95.

5. Kalff JC, Wehner S, Litkouhi B. Postoperative ileus. In: Post TW, editor. UpToDate [Internet]. Waltham (MA): UpToDate; 2017 Jul 17 [cited 2017 Nov 20]. Available from: www.uptodate.com Subscription required. 6. Iwarzon M, Gardulf A, Lindberg G. Functional status, health-related quality of life and symptom severity in patients with chronic intestinal pseudo-obstruction and enteric dysmotility. Scand J Gastroenterol. 2009;44(6):700-7.

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. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774262 8. Camilleri M. Chronic intestinal pseudo-obstruction. In: Post TW, editor. [Internet]. Waltham (MA): UpToDate; 2016 Jul 18 [cited 2017 Nov 16]. Available from: www.uptodate.com Subscription required. 9. Cagir B. Intestinal pseudo-obstruction [Internet]. New York: Medscape; 2016 Jan 5. [cited 2017 Nov 20]. Available from: https://emedicine.medscape.com/article/2162306- overview#a7 10. Bharucha AE. Epidemiology and natural history of gastroparesis. Gastroenterol Clin North Am [Internet]. 2015 Mar [cited 2017 Nov 16];44(1):9-19. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323583 11. Wald A. Management of chronic constipation in adults. In: Post TW, editor. UpToDate [Internet]. Waltham (MA): UpToDate; 2017 Feb 1 [cited 2017 Nov 16]. Available from: www.uptodate.com Subscription required. 12. Jiang C, Xu Q, Wen X, Sun H. Current developments in pharmacological therapeutics for chronic constipation. Acta Pharm Sin B [Inte]. 2015 Jul;5(4):300-9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629408 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 ileus. 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: https://www.cadth.ca/sites/default/files/cdr/complete/cdr_complete_Resotran_July- 23-12.pdf

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 9

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 from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930296 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: prucalopride, a colonic pro-motility agent, reduces the duration of post-operative ileus after elective gastrointestinal surgery. Aliment Pharmacol Ther. 2016 Apr;43(7):778-89.

25. Emmanuel AV, Kamm MA, Roy AJ, Kerstens R, Vandeplassche L. Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction--a double-blind, placebo-controlled, cross-over, multiple n = 1 study. Aliment Pharmacol Ther [Internet]. 2012 Jan [cited 2017 Nov 9];35(1):48-55. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298655

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 10

Appendix 1: Selection of Included Studies

343 citations identified from electronic literature search and screened

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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 11

Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Systematic Reviews First Author, Objectives Inclusion Criteria Exclusion Studies included Year, Criteria Country Literature Search Strategy Main outcomes

Shin,21 2014, US “To assess the effects of highly “This review was Trials not 13 RCTs selective 5-HT4 agonists limited to RCTs satisfying 11 prucalopride (prucalopride, velusetrag or studying the effects of inclusion criteria 1 velusetrag naronapride) on patient-important any HS 5-HT4 receptor clinical efficacy outcomes and agonist including, but 1naronapride safety in adults with CC” (p 239) not limited to, prucalopride, Efficacy: velusetrag and We searched the medical naronapride in ≥3 CSBM per week literature in January 2013 using adults with CC” (p 240) Increase over baseline by MEDLINE/Pubmed, Embase, ≥1 CSBM per week

Cochrane Library, and Web of Science/Scopus for randomised, Duration of therapy Quality of life: controlled trials (maximum 12 weeks)

of highly selective 5-HT4 agonists in adults with CC, with no PAC-QOL (PAC-QOL minimum questionnaire) duration of therapy (maximum 12 weeks) or date limitations (p 239). 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 Phase II and phase III Trials not 16 RCTs (3943 patients) prucalopride in the management randomised, satisfying of chronic constipation based inclusion criteria placebo-controlled trials Efficacy: upon the principles of meta- (RCT) reported the analysis using data reported in effectiveness of Frequency of SBM per the published randomized, prucalopride in patients week controlled trials” (p 412) with chronic constipation (duration Adverse events “Electronic medical databases of prucalopride use such as the Medline, EMBASE, ranged from 1-12 weeks) Cochrane Colorectal Cancer Group Controlled Trial Register, Pain...and the Cochrane Central Register of Controlled Trials (CENTRAL) in the

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 12

First Author, Objectives Inclusion Criteria Exclusion Studies included Year, Criteria Country Literature Search Strategy 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, “To compare efficacy of Phase IIB and phase III Trials not satisfied 21 RCTs (9189 patients) US pharmacotherapies randomised, inclusion criteria 9 prucalopride for chronic idiopathic constipation placebo-controlled trials 3 lubiprostone (CIC) based on comparisons to (RCT) of ≥4 weeks’ placebo using Bayesian network treatment 3 linaclotide meta-analysis” (p1611) for CIC in adults with 2 tegaserod functional 1 velusetrag “We conducted searches constipation 1 elobixibat (inception to May 2015) of 1 bisacodyl MEDLINE, EMBASE, Scopus and 1 sodium picosulphate Cochrane (NaP) Central, as well as original data

from authors or drug Primary outcomes: companies for the medications used for CIC” (p 1611) ≥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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 13

Table 3: Characteristics of Included Clinical Studies

First Author, Study Design Interventions/Co Patients Main Outcomes Year, Country Study Objectives mparators

Gong,24 2016, Phase II double-blind RCT Prucalopride 2 110 patients Primary outcome: China mg/day undergoing elective Time to defecation “To evaluate the effect and gastrointestinal safety of prucalopride on Placebo surgery (mean age 37 Secondary outcomes: post-operative ileus and for prucalopride, 38 for Time to first passage of surgical outcomes after placebo) flatus elective gastrointestinal Post-operative length of stay surgery” (p 778) Surgical complications Inflammatory parameters Adverse events

Emmanuel,25 Randomized, double-blind, Prucalopride2- 7 patients with chronic Efficacy: 2012, UK, placebo-controlled cross- 3mg/day idiopathic chronic Symptoms using diary Belgium, over trial intestinal pseudo- recording (pain, vomiting, Australia Placebo obstruction (mean age nausea, bloating) To evaluate the effect and 42 years) Rescue analgesia use safety of prucalopride on Body weight chronic intestinal pseudo- Patients were treated obstruction for periods of12 weeks Adverse events 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).

RCT = randomized controlled trial

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 14

Appendix 3: Critical Appraisal of Included Publications Table 4: Summary of Critical Appraisal of Included Studies First Author, Strengths Limitations Publication Year Critical appraisal of included systematic review (AMSTAR 219) Shin21  a priori design provided  assessment of publication bias not performed  independent studies selection and data  list of excluded studies not provided extraction procedure in place  heterogeneity across trials in study design  comprehensive literature search performed (phase II and III), duration of intervention, and  list of included studies, studies characteristics provided follow-up periods  quality assessment of included studies provided and used in formulating conclusions  conflict of interest stated Sajid22  a priori design provided  assessment of publication bias not performed  independent studies selection and data  list of excluded studies not provided extraction procedure in place  heterogeneity across trials in study design  comprehensive literature search performed (phase II and III), duration of intervention, and  list of included studies, studies characteristics provided follow-up periods  quality assessment of included studies performed and used in formulating conclusions  conflict of interest stated Nelson23  a priori design provided  assessment of publication bias not performed  independent studies selection and data  list of excluded studies not provided extraction procedure in place  heterogeneity across trials in study design  comprehensive literature search performed (phase II and III), duration of intervention, and  list of included studies, studies characteristics provided follow-up periods  quality assessment of included studies provided and used in formulating conclusions  conflict of interest stated Critical appraisal of included clinical trial (Downs and Black20)

Gong24  randomized controlled trial  single-centre study with relatively small sample  both the investigator and the patient were size 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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 15

First Author, Strengths Limitations Publication Year clinically important effect

Emmanuel25  randomized controlled trial  single-centre study with insufficient power to  both the investigator and the patient detect a clinically important effect 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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 16

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 “Demonstration of efficacy on patient-important outcomes and a All drugs were superior to placebo favourable safety profile support the continued use and development of Prucalopride highly selective 5–HT4 agonists in RR 1.63; 95% CI 1.07-2.49 (data from 9 trials) the treatment of chronic constipation” (p 239). 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)

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 17

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: “Prucalopride is clinically a beneficial pharmacotherapy for Prucalopride1 mg chronic constipation and its routine SMD 0.42 (95% CI, 0.18-0.66); P = 0.006 (data from 5 trials) use may be considered in patients with chronic simple laxative- Prucalopride 2 mg resistant constipation” (p 412) SMD 0.34 (95% CI, 0.11-0.56); P = 0.003 (data from 9 trials) “The findings of the current study Prucalopride 4 mg are pertinent to only that group of SMD 0.33 (95% CI, 0.22-0.44); P = 0.00001 (data from 5 trials) patients which have failed basic laxative therapy (lactulose, Adverse events vs placebo: ispaghula husk, and senna), life style modifications and stronger The most commonly reported adverse events : headache, nausea, abdominal pain or laxatives therapy (macrogol, cramps, and diarrhea bisacodyl or glycerol suppository, sodium phosphate, and arachis oil Prucalopride 1 mg enema), and therefore, conclusion OR 2.02; 95% CI, 1.10-3.72; P = 0.020 (data from 7 trials) cannot be generalized to all types of constipation and on group of Prucalopride 2 mg patients where early treatment is not OR 1.76; 95% CI, 1.33-2.34; P< 0.0001(data from 13 trials) optimally tested” (p 419)

Prucalopride 4 mg OR 1.52; 95% CI, 1.13-2.05; P = 0.006 (data from 7 trials) Nelson23 (Systematic Review) ≥3 CSBM/week “Our study has shown that each drug used in the treatment of CIC is All drugs were superior to placebo superior to placebo, based on the published randomised, Prucalopride placebo-controlled trials” (p 1617) RR 1.85; 95% CI 1.35-2.54 (data from 9 trials) “No drug was superior at improving Velusetrag the primary end points on network RR 4.86; 95% CI 2.02-11.71 (data from 1 trial) meta-analysis” (p 1611)

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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 18

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)

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 19

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 is a safe and effective Prucalopride 65.0 h treatment to reduce post-operative Placebo 94.5 h, P = 0.001 ileus and systemic inflammation without affecting post-operative Passage of flatus complications in patients Prucalopride 53.0 h undergoing elective gastrointestinal Placebo 73.0 h, P<0.001 surgery” (p 778)

Post-operative length of stay Prucalopride 7.0 days Placebo 8.0 days, P = 0.001

The number of patients with prolonged ileus (>5 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),

Emmanuel25 (Clinical Trial) 7 patients participated (3 discontinued, 2 due to study length, and 1 on prucalopride due to “Prucalopride relieves symptoms in unrelated malnutrition and bronchopneumonia) selected patients with chronic 4 patients completed the study pseudo-obstruction” (p 48) 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)

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 20

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

SUMMARY WITH CRITICAL APPRAISAL Prucalopride f or Gastrointestinal Motility Disorders 21