Rationale and design of a multicenter, single-group, open-label trial aiming at investigating the effectiveness of elobixibat for loss of defecation desire in patients with chronic constipation

Atsushi Yamamoto, Takaomi Kessoku, Kosuke Tanaka, Kota Takahashi, Yuki Kasai, Anna Ozaki, Michihiro Iwaki, Takashi Kobayashi, Tsutomu Yoshihara, Noboru Misawa, Kanji Ohkuma, Akiko Fuyuki, Takuma Higurashi, Kunihiro Hosono, Masato Yoneda, Tomoyuki Iwasaki, Takeo Kurihashi, Machiko Nakatogawa, Ayao Suzuki, Masataka Taguri, Shunsuke Oyamada, Keisuke Ariyoshi, Noritoshi Kobayashi, Yasushi Ichikawa, Atsushi Nakajima, Atsushi Yamamoto, Takaomi Kessoku, Kosuke Tanaka, Kota Takahashi, Yuki Kasai, Anna Ozaki, Michihiro Iwaki, Takashi Kobayashi, Tsutomu Yoshihara, Noboru Misawa, Kanji Ohkuma, Akiko Fuyuki, Takuma Higurashi, Kunihiro Hosono, Masato Yoneda, Tomoyuki Iwasaki, Takeo Kurihashi, Machiko Nakatogawa, Ayao Suzuki, Masataka Taguri, Shunsuke Oyamada, Keisuke Ariyoshi, Noritoshi Kobayashi, Yasushi Ichikawa, Atsushi Nakajima

Abstract

Background: Approximately 60% of patients with chronic constipation (CC) have a significantly higher rate of loss of defecation desire (LODD). Bile acids are expected to have a restorative effect on defecation desire (DD) because they lower the rectal sensory threshold, which is an objective index of DD. Elobixibat (EXB) specifically inhibits the ileal bile acid transporter/apical sodium-dependent bile acid transporter, which is a transporter involved in the reabsorption of bile acids in the terminal ileum. This study aims to investigate the LODD improvement rate in patients with CC after 4 weeks of EXB treatment.

Methods: A total of 40 adult patients with CC who meet the eligibility criteria will be enrolled. Patients will receive oral EXB (10 mg/day) for 4 weeks. A patient diary will be provided daily at 4 weeks after treatment. The primary endpoint will be the percentage LODD improvement at week 4 of the treatment period from week 2 of the observation period using questionnaires.

Ethics and dissemination: Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board prior to participant enrolment (approval number: CRB21-008). The results of this study will be submitted for publication in international peer-reviewed journals, and key findings will be presented at international scientific conferences. Participants desiring the results of this study will be directly contacted for data dissemination.

Trial registration: This trial was registered at ClinicalTrials.gov (NCT05165199).

Protocol version: 1.0, September 21, 2021.

Keywords: Bile acid; Chronic constipation; Defecation desire; Elobixibat; Loss of defecation desire.

Conflict of interest statement

ANa reports grants and research support from Gilead, Mylan EPD, EA Pharma, Kowa, Taisho, and Biofermin. ANa is a consulting adviser for Gilead, Boehringer Ingelheim, BMS, Kowa, Astellas, EA Pharma, and Mylan EPD. The other authors declare no conflicts of interest.

© 2022 The Authors.

Figures

Fig. 1
Fig. 1
Study design.

References

    1. Belsey J.D., Geraint M., Dixon T.A. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int. J. Clin. Pract. 2010;64:944–955. doi: 10.1111/j.1742-1241.2010.02397.x.
    1. Wald A., Scarpignato C., Kamm M.A., et al. The burden of constipation on quality of life: results of a multinational survey. Aliment. Pharmacol. Ther. 2007;26:227–236. doi: 10.1111/j.1365-2036.2007.03376.x.
    1. Koloski N.A., Jones M., Wai R., Gill R.S., Byles J., Talley N.J. Impact of persistent constipation on health-related quality of life and mortality in older community-dwelling women. Am. J. Gastroenterol. 2013;108:1152–1158. doi: 10.1038/ajg.2013.137.
    1. Salmoirago-Blotcher E., Crawford S., Jackson E., Ockene J., Ockene I. Constipation and risk of cardiovascular disease among postmenopausal women. Am. J. Med. 2011;124:714–723. doi: 10.1016/j.amjmed.2011.03.026.
    1. Sumida K., Molnar M.Z., Potukuchi P.K., et al. Constipation and risk of death and cardiovascular events. Atherosclerosis. 2019;281:114–120. doi: 10.1016/j.atherosclerosis.2018.12.021.
    1. Sundbøll J., Szépligeti S.K., Adelborg K., Szentkúti P., Gregersen H., Sørensen H.T. Constipation and risk of cardiovascular diseases: a Danish population-based matched cohort study. BMJ Open. 2020;10 doi: 10.1136/bmjopen-2020-037080.
    1. Chang J.Y., Locke G.R., 3rd, McNally M.A., et al. Impact of functional gastrointestinal disorders on survival in the community. Am. J. Gastroenterol. 2010;105:822–832. doi: 10.1038/ajg.2010.40.
    1. Ohkubo H., Takatsu T., Yoshihara T., et al. Difference in DD between patients with and without chronic constipation: a large-scale Internet survey. Clin. Transl. Gastroenterol. 2020;11 doi: 10.14309/ctg.0000000000000230.
    1. Acosta A., Camilleri M. Elobixibat and its potential role in chronic idiopathic constipation. Ther. Adv. Gastroenterol. 2014;7:167–175. doi: 10.1177/1756283X14528269.
    1. Bampton P.A., Dinning P.G., Kennedy M.L., Lubowski D.Z., Cook I.J. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am. J. Physiol. Gastrointest. Liver Physiol. 2002;282:G443–G449. doi: 10.1152/ajpgi.00194.2001.
    1. Edwards C.A., Brown S., Baxter A.J., Bannister J.J., Read N.W. Effect of bile acid on anorectal function in man. Gut. 1989;30:383–386. doi: 10.1136/gut.30.3.383.
    1. Des Jarlais D.C., Lyles C., Crepaz N. TREND Group, Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement. Am. J. Publ. Health. 2004;94:361–366. doi: 10.2105/ajph.94.3.361.
    1. Nakajima A., Seki M., Taniguchi S., et al. Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial. Lancet Gastroenterol. Hepatol. 2018;3:537–547. doi: 10.1016/S2468-1253(18)30123-7.
    1. Mori S., Tomita T., Fujimura K., et al. A randomized double-blind placebo-controlled trial on the effect of magnesium oxide in patients with chronic constipation. J. Neurogastroenterol. Motil. 2019;25:563–575. doi: 10.5056/jnm18194.
    1. Fukudo S., Hongo M., Kaneko H., Takano M., Ueno R. Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation. Clin. Gastroenterol. Hepatol. 2015;13:294–301. doi: 10.1016/j.cgh.2014.08.026. e5.
    1. Lembo A.J., Schneier H.A., Shiff S.J., et al. Two randomized trials of linaclotide for chronic constipation. N. Engl. J. Med. 2011;365:527–536. doi: 10.1056/NEJMoa1010863.
    1. Cheng J., Li L., Xu F., Xu Y., Lin L., Chen J.D.Z. Poststroke constipation is associated with impaired rectal sensation. Am. J. Gastroenterol. 2020;115:105–114. doi: 10.14309/ajg.0000000000000479.
    1. Vollebregt P.F., Burgell R.E., Hooper R.L., Knowles C.H., Scott S.M. Clinical impact of rectal hyposensitivity: a cross-sectional study of 2,876 patients with refractory functional constipation. Am. J. Gastroenterol. 2021;116:758–768. doi: 10.14309/ajg.0000000000001039.
    1. Iwai N., Kume Y., Kimura O., Ono S., Aoi S., Tsuda T. Effects of herbal medicine Dai-Kenchu-to on anorectal function in children with severe constipation. Eur. J. Pediatr. Surg. 2007;17:115–118. doi: 10.1055/s-2007-965016.
    1. Iturrino J., Camilleri M., Wong B.S., Linker Nord S.J., Burton D., Zinsmeister A.R. Randomised clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit, anorectal and bowel function in female patients with functional constipation. Aliment. Pharmacol. Ther. 2013;37:776–785. doi: 10.1111/apt.12264.
    1. Whitehead W.E., Palsson O.S., Gangarosa L., Turner M., Tucker J. Lubiprostone does not influence visceral pain thresholds in patients with irritable bowel syndrome. Neuro Gastroenterol. Motil. 2011;23 doi: 10.1111/j.1365-2982.2011.01776.x. 944–e400.
    1. Dinning P.G., Bampton P.A., Kennedy M.L., Lubowski D.Z., King D., Cook I.J. Impaired proximal colonic motor response to rectal mechanical and chemical stimulation in obstructed defecation. Dis. Colon Rectum. 2005;48:1777–1784. doi: 10.1007/s10350-005-0087-8.
    1. Misawa N., Higurashi T., Takatsu T., et al. The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota. Aliment. Pharmacol. Ther. 2020;52:821–828. doi: 10.1111/apt.15950.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera