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Clinical Trial
. 2021 Feb 1;116(2):354-361.
doi: 10.14309/ajg.0000000000000967.

Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

William D Chey  1 , Gregory S Sayuk  2 , Wilmin Bartolini  3 , David S Reasner  4 , Susan M Fox  5 , Wieslaw Bochenek  5 , Ramesh Boinpally  5 , Elizabeth Shea  3 , Kenneth Tripp  6 , Niels Borgstein  3
Affiliations
Clinical Trial

Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

William D Chey et al. Am J Gastroenterol. .

Abstract

Introduction: Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects.

Methods: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate.

Results: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo.

Discussion: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

Trial registration: ClinicalTrials.gov NCT02559206.

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Conflict of interest statement

Guarantor of the article: Wilmin Bartolini, PhD.

Specific author contributions: W.B., D.S.R., S.M.F., W.B., and K.T. contributed to the conception and design of the study. D.S.R. and K.T. contributed to the analysis of the data. All authors contributed to the interpretation of the data and drafting, critical revision, and final approval of the manuscript.

Financial support: This study was sponsored by Allergan plc (before acquisition by AbbVie, Inc.) and/or AbbVie, Inc. and Ironwood Pharmaceuticals, Inc. Writing and editorial assistance was provided to the authors by Brittany Y. Jarrett, PhD, and Rebecca Fletcher, BA(Hons), of Complete HealthVizion, Inc., Chicago, IL, and funded by Allergan plc and/or AbbVie, Inc., and Ironwood Pharmaceuticals, Inc. All authors met the ICJME authorship criteria. Neither honoraria nor payments were made for authorship.

Potential competing interests: Financial arrangements of the authors with companies whose products might be related to this report are listed as follows, as declared by the authors: W.D.C. has served as a consultant for Allergan plc (before acquisition by AbbVie, Inc.), Alnylam, Arena, Biomerica, Ironwood Pharmaceuticals, Inc., IM Health, QOL Medical, Outpost, Ritter, Salix Pharmaceuticals, Takeda, and Urovant Sciences and received research grants from Biomerica, Ironwood Pharmaceuticals, Inc., Commonwealth Diagnostic International, QOL Medical, Salix, Urovant Sciences, Vibrant, and Zespri. G.S.S. has served as a consultant and speaker for Allergan plc (before acquisition by AbbVie, Inc.), Ironwood Pharmaceuticals, Inc., and Salix Pharmaceuticals. W.B., E.S., and N.B. are employees of Ironwood Pharmaceuticals, Inc., and have held or currently hold stock and stock options. D.S.R. and K.T. are former employees of Ironwood Pharmaceuticals, Inc., and have held or currently hold stock and stock options. S.M.F., W.B., and R.B. are employees of AbbVie, Inc., and hold stock and stock options.

Trial registration: ClinicalTrials.gov (NCT02559206).

Figures

Figure 1.
Figure 1.
Study design. DR1, delayed-release formulation 1; IR, immediate-release formulation; LIN, linaclotide; PBO, placebo.
Figure 2.
Figure 2.
Weekly CFB in abdominal pain. Treatment effects of (a) LIN DR1 30 μg, 100 μg, and 300 μg and (b) MD-7246 30 μg, 100 μg, and 300 μg are shown with respect to LIN 290 μg IR and PBO, with 12-week LS mean differences vs PBO reported in each legend. All 8 treatment groups were evaluated in a single model, wherein treatment group was included as a fixed effect. CFB, change from baseline; CI, confidence interval; DR1, delayed-release formulation 1; IR, immediate-release formulation; LIN, linaclotide; LS, least-squares; PBO, placebo.
Figure 3.
Figure 3.
Weekly CFB in CSBM frequency. Treatment effects of (a) LIN DR1 30 μg, 100 μg, and 300 μg and (b) MD-7246 30 μg, 100 μg, and 300 μg are shown with respect to LIN 290 μg IR and PBO, with 12-week LS mean differences vs PBO reported in each legend.All 8 treatment groups were evaluated in a single model, wherein treatment group was included as a fixed effect. CFB, change from baseline; CI, confidence interval; CSBM, complete spontaneous bowel movement; DR1, delayed-release formulation 1; IR, immediate-release formulation; LIN, linaclotide; LS, least-squares; PBO, placebo.
Figure 4.
Figure 4.
Percentage of patients with diarrhea TEAEs, including those leading to discontinuation. The proportion of patients with diarrhea TEAEs leading to discontinuation (grey) is shown as a subset of the total population with ≥1 diarrhea TEAE in each treatment group. DR1, delayed-release formulation 1; IR, immediate-release formulation; TEAE, treatment-emergent adverse event.
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References

    1. Drossman DA. Functional gastrointestinal disorders: History, pathophysiology, clinical features, and Rome IV. Gastroenterology 2016;150:1262–79. - PubMed
    1. Lacy BE, Mearin F, Chang L et al. . Bowel disorders. Gastroenterology 2016;150:1393–407.e5. - PubMed
    1. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: A meta-analysis. Clin Gastroenterol Hepatol 2012;10:712–21. - PubMed
    1. Drossman DA, Morris CB, Schneck S et al. . International survey of patients with IBS: Symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol 2009;43:541–50. - PMC - PubMed
    1. Ballou S, McMahon C, Lee H-N et al. . Effects of irritable bowel syndrome on daily activities vary among subtypes based on results from the IBS in America survey. Clin Gastroenterol Hepatol 2019;17:2471–8. - PMC - PubMed

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