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Confidential: for Review Only 9 Address for Correspondence: Michael Camilleri, M.D Page 1 of 72 Gut Nelson, Camilleri, et al. - 1 - 1 2 3 gim/c/c/man/Nelson_CIC_systematic_review_4_10_16_without_figures.docx 4 5 gim/c/c/man/Nelson_CIC_systematic_review_4_10_16_without_figures_CLEAN.docx 6 gim/c/c/man/Nelson_CIC_systematic_review_3_10_16_Fig1.tif thru Fig3D.tif 7 4-14-16 8 ForConfidential: re-submission to GUT For Review Only 9 10 11 12 Comparison of Efficacy of Pharmacological Treatments for 13 Chronic Idiopathic Constipation: 14 15 A Systematic Review and Network Meta-analysis 16 17 Alfred D. Nelson, M.B.B.S. 18 19 Michael Camilleri, M.D. 20 Sakkarin Chirapongsathorn, M.D., M.Sc. 21 22 Priya Vijayvargiya, M.D. 23 Nelson Valentin, B.S. 24 Andrea Shin, M.D., M.Sc.* 25 26 Patricia J. Erwin # 27 Zhen Wang, Ph.D. 28 M. Hassan Murad, M.D.# 29 30 31 From 32 Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and 33 #Mayo Clinic Evidence-Based Practice Center, Mayo Clinic, Rochester, MN 55905 34 *Dr. Shin’s current affiliation: Indiana University, Indianapolis, IN 35 36 37 38 Running title: Network meta-analysis of pharmacological agents for treatment of CIC 39 40 Word count: 3745 (excluding abstract, summary box, acknowledgements, disclosures, 41 references, table and figure legends) 42 43 44 Key words: bisacodyl, elobixibat, linaclotide, lubiprostone, picosulfate, polyethylene glycol, 45 prucalopride, tegaserod, velusetrag 46 47 Abbreviations: 48 49 chronic idiopathic constipation (CIC) 50 numbers needed to treat (NNT) 51 sodium picosulfate (NaP) 52 polyethylene glycol (PEG) 53 complete spontaneous bowel movements (CSBM) 54 spontaneous bowel movements (SBM) 55 56 weighted mean difference (WMD) 57 confidence interval (CI) 58 _________________________________________________________________________________ 59 60 This is the author's manuscript of the article published in final edited form as: Nelson, A. D., Camilleri, M., Chirapongsathorn, S., Vijayvargiya, P., Valentin, N., Shin, A., … Murad, M. H. (2016). Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis. Gut, gutjnl-2016-311835. https://doi.org/10.1136/gutjnl-2016-311835 Gut Page 2 of 72 Nelson, Camilleri, et al. - 2 - 1 2 3 serotonin or 5-hydroxytryptamine (5HT) 4 5 normal transit constipation (NTC) 6 slow transit constipation (STC) 7 high amplitude propagated contractions (HAPC) 8 Confidential: For Review Only 9 Address for correspondence: Michael Camilleri, M.D. 10 11 Mayo Clinic 12 200 First St. S.W. 13 Charlton Bldg., Rm. 8-110 14 Rochester, MN 55905 15 Tele: 507-266-2305 16 Email: [email protected] 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/gut Page 3 of 72 Gut Nelson, Camilleri, et al. - 3 - 1 2 3 ABSTRACT 4 5 6 Objective: To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) 7 8 basedConfidential: on comparisons to placebo using Bayesian For netw Reviework meta-analysis. Only 9 10 11 Data Sources: We conducted searches (inception to May 2015) of MEDLINE, EMBASE, 12 13 Scopus and Cochrane Central, as well as original data from authors or drug companies for the 14 15 medications used for CIC. 16 17 ≥ 18 Study Selection: Phase IIB and phase III randomized, placebo-controlled trials (RCT) of 4 19 20 weeks’ treatment for CIC in adults with Rome II or III criteria for functional constipation; trials 21 22 included at least 1 of 4 endpoints. 23 24 25 Data Extraction and Synthesis: Two investigators independently evaluated all full text articles 26 27 that met inclusion criteria and extracted data for primary and secondary endpoints, risk of bias 28 29 and quality of evidence. 30 31 32 Outcomes: Primary endpoints were ≥3 complete spontaneous bowel movements (CSBM)/week 33 34 and increase over baseline by ≥1 CSBM/week. Secondary endpoints were change from baseline 35 36 37 (∆b) in the number of SBM/week and ∆b CSBM/week. 38 39 Results: Twenty-one RCTs (9189 patients) met inclusion and endpoint criteria: 9 prucalopride, 3 40 41 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium 42 43 44 picosulphate (NaP). All pre-specified endpoints were unavailable in 4 polyethylene glycol 45 46 studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 47 48 CSBM/week endpoint. No drug was superior at improving the primary endpoints on network 49 50 51 meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary endpoint, ∆b in 52 53 number of SBM/week. 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/gut Gut Page 4 of 72 Nelson, Camilleri, et al. - 4 - 1 2 3 Conclusions: Current drugs for CIC show similar efficacy. Bisacodyl may be superior to 4 5 6 prescription medications for ∆b in the number of SBM/week in CIC. 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/gut Page 5 of 72 Gut Nelson, Camilleri, et al. - 5 - 1 2 3 SUMMARY BOX 4 5 6 What is already known about this subject? 7 8 - FiftyConfidential: percent of patients with chronic idiopathi Forc constipation Review (CIC) are not Onlycompletely satisfied 9 10 11 with treatment, especially with fiber and laxatives. 12 13 - The number needed to treat (NNT), estimated from placebo-controlled clinical trials in CIC 14 15 comparing pharmacological therapies to placebo, have been reported as follows: osmotic and 16 17 18 stimulant laxative, NNT 3; lubiprostone, NNT 4; and prucalopride and linaclotide, both NNT 6. 19 20 - The absence of direct comparisons between different drug classes limits comparison of 21 22 efficacy among treatments. 23 24 25 What are the new findings? 26 27 - Current drugs for CIC show similar efficacy for primary endpoints, which were ≥3 complete 28 29 spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. 30 31 32 - Bisacodyl may be superior to prescription medications for change from baseline ( ∆b) 33 34 SBM/week in CIC and in comparison with some of the drugs in ∆b CSBM/week. 35 36 37 How might it impact on clinical practice in the foreseeable future? 38 39 - Head-to-head trials of active agents are necessary to determine the optimal selection of 40 41 pharmacological agents for CIC. 42 43 44 - Alternatively, first line medications for patients with CIC should be according to the 45 46 pathophysiology in order to increase efficacy, such as prokinetics for patients with documented 47 48 slow transit constipation in the absence of rectal evacuation disorders. 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/gut Gut Page 6 of 72 Nelson, Camilleri, et al. - 6 - 1 2 3 INTRODUCTION 4 5 6 The estimated global prevalence of chronic idiopathic constipation (CIC) in adults is 7 8 14%.[1]Confidential: It is usually diagnosed using Rome For III symp tomReview criteria,[2] is about Onlytwice as common in 9 10 11 women and more prevalent over 65 years of age, significantly impacts quality of life, and 12 13 constitutes a significant financial burden.[3] Treatment of constipation [4] usually starts with 14 15 nonpharmacological agents like fiber (soluble in preference to nonsoluble fiber and is followed 16 17 18 by pharmacological agents if there is no response to fiber.[5] Polyethylene glycol, an osmotic 19 20 laxative, increases the mean number of stools per week more effectively than placebo or 21 22 lactulose in adults with CIC, based on direct meta-analyses.[6] It is estimated that about 50% of 23 24 25 patients with CIC were not completely satisfied with treatment due to lack of efficacy or safety 26 27 concerns, especially with fiber and laxatives (both stimulant and osmotic). 28 29 Therefore, this appraisal of the relative efficacy of pharmacotherapies for chronic CIC is 30 31 32 clinically relevant. The pharmacological classes of the medications used for CIC are: diphenyl 33 34 methanes or derivatives (bisacodyl and sodium picosulphate), 5-HT 4 receptor agonists 35 36 37 (prucalopride, tegaserod and velusetrag), guanylate cyclase C receptor agonist (linaclotide), 38 39 chloride channel type 2 opener (lubiprostone) and apical sodium bile acid, (also known as ileal 40 41 bile acid transport) inhibitor (elobixibat). 42 43 44 The numbers needed to treat (NNT), estimated from placebo-controlled clinical trials 45 46 comparing these medications to placebo in CIC, were reported as follows: osmotic and stimulant 47 48 laxative, NNT 3; lubiprostone, NNT 4; and prucalopride and linaclotide, both NNT 6.[6] This 49 50 51 might suggest differences in efficacy of the different drug classes; however, this assessment was 52 53 based on failure to respond to therapy, and vastly different endpoints were used in individual 54 55 studies. 56 57 58 59 60 https://mc.manuscriptcentral.com/gut Page 7 of 72 Gut Nelson, Camilleri, et al. - 7 - 1 2 3 The absence of direct comparisons between different drug classes limits comparison of 4 5 6 efficacy among treatments to the endpoints currently recommended by the US Food and Drug 7 8 AdministrationConfidential: and is consistent with those For of European Review Medicines Agency.[7] Only Therefore, our 9 10 11 aim was to compare the efficacy of drugs for CIC based on results of each drug compared to 12 13 placebo using Bayesian network meta-analysis and endpoints consistent with current regulatory 14 15 agency recommendations.
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