Two randomized trials of linaclotide for chronic constipation
Open accessAbstract
BACKGROUND: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. METHODS: We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. RESULTS: For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. CONCLUSIONS: In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).
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Use of linaclotide leads to increases in CSBMs per week (MD 1.37, 95% CI 1.07-1.95) and SBMs per week (MD 1.97, 95% CI 1.59-2.36), improves stool consistency (MD 1.25, 95% CI 1.1-1.39 higher), and increases rates of global relief (RR 1.96, 95% CI 1.63-2.35).
“The use of linaclotide leads to increases in the number of CSBMs per week (MD 1.37, 95% CI 1.07-1.95) and SBMs per week (MD 1.97, 95% CI 1.59-2.36), improves stool consistency (MD 1.25, 95% CI 1.1-1.39 higher), and increases the rates of global relief (RR 1.96, 95% CI 1.63-2.35).”
From American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation (2023) · cites this paper as [64]
The Secondary Efficacy End Points and Discussion sections report that linaclotide increased weekly CSBMs and SBMs and improved stool consistency versus placebo; the Additional Efficacy End Points section reports greater constipation relief. The paper reports results by trial and dose, but our copy does not give the cited pooled mean differences, risk ratio, or confidence intervals, so those numerical estimates are not verified. (LLM, conf=0.88)
Experimental — accuracy not yet measuredUse of linaclotide might improve PAC-QOL scores compared with placebo; however, data could not be pooled.
“The use of linaclotide might improve the PAC-QOL scores compared with placebo; 64 however, data could not be pooled.”
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BackgroundBarboza, J., Okun, M. S., & Moshiree, B. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2015.1086747 · Cited by 78 · see citing works
“Guanylate Cyclase C Receptor Peptide: Promotes the generation of cyclic guanosine monophosphate that secretes chloride and bicarbonate into the intestinal lumen, increasing luminal fluid secretion and accelerating intestinal transit [38] Linaclotide: 145 -- 290 mcg QD Not evaluated in PD.”
BackgroundDeMicco, M., Barrow, L., Hickey, B., Shailubhai, K., & Griffin, P. (2017) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x17734697 · Cited by 74 · see citing works
Schoenfeld, P., Lacy, B. E., Chey, W. D., Lembo, A. J., Kurtz, C. B., Reasner, D. S., Bochenek, W. J., Tripp, K. J., Currie, M. G., Fox, S. M., et al. (2017) · The American Journal of Gastroenterology · doi:10.1038/ajg.2017.230 · Cited by 75 · see citing works
Self-citationMeasuring response in the gastrointestinal tract in systemic sclerosis
Khanna, D., Nagaraja, V., Gladue, H. S., Chey, W. D., Pimentel, M., & Frech, T. (2013) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000434668.32150.e5 · Cited by 73 · see citing works
“Outcome measures administered at baseline and 12 weeks are: proportion of three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks [57], and GIT 2.”
MethodGastrointestinal involvement in systemic sclerosis: An updated review
Nassar, M., Ghernautan, V., Nso, N., Nyabera, A., Castillo, F. J. C., Tu, W., Medina, L., Ciobanu, C., Alfishawy, M., Rizzo, V., et al. (2022) · Medicine · doi:10.1097/md.0000000000031780 · Cited by 73 · see citing works
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Guanylate cyclase-C receptor activation: unexpected biology
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“Lembo et al., 2011.”
Medical Management of Constipation in Elderly Patients: Systematic Review
Kang, S. J., Cho, Y. S., Lee, T. H., Kim, S., Ryu, H. S., Kim, J., Park, S., Lee, Y. J., & Shin, J. E. (2021) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm20210 · Cited by 64 · see citing works
Chronic Constipation: a Review of Current Literature
Sbahi, H., & Cash, B. D. (2015) · Current Gastroenterology Reports · doi:10.1007/s11894-015-0471-z · Cited by 62 · see citing works
Wilson, C., Lin, J. E., Li, P., Snook, A. E., Gong, J., Sato, T., Liu, C., Girondo, M. A., Rui, H., Hyslop, T., et al. (2014) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-14-0440 · Cited by 61 · see citing works
“These translational considerations are underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide to treat patients with irritable bowel syndrome-constipation type (39), and the initiation of a clinical program to explore its utility in preventing colorectal transformation in humans (ClinicalT…”
BackgroundLin, J. E., Colón‐González, F., Blomain, E. S., Kim, G. W., Aing, A., Stoecker, B. A., Rock, J., Snook, A. E., Zhan, T., Hyslop, T., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-1467-t · Cited by 60 · see citing works
“GUCY2C ligand, received FDA approval for the treatment of constipation-type irritable bowel syndrome (25).”
An Update of Pharmacological Management in Children with Functional Constipation
de Geus, A., Koppen, I. J. N., Flint, R. B., Benninga, M. A., & Tabbers, M. M. (2023) · Pediatric Drugs · doi:10.1007/s40272-023-00563-0 · Cited by 70 · see citing works
“Linaclotide has been proven to be safe and efficient for the treatment of FC and irritable bowel syndrome with constipation in adults [84, 85].”
BackgroundAgents that act luminally to treat diarrhoea and constipation
Menees, S. B., Saad, R. J., & Chey, W. D. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2012.162 · Cited by 57 · see citing works
Sinagra, E., Morreale, G., Mohammadian, G., Fusco, G., Guarnotta, V., Tomasello, G., Cappello, F., Rossi, F., Amvrosiadis, G., & Raimondo, D. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i36.6593 · Cited by 52 · see citing works
Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21
Basu, N., Saha, S., Khan, I., Ramachandra, S. G., & Visweswariah, S. S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.511311 · Cited by 57 · see citing works
“The GC-C agonist linaclotide is currently a drug of choice for the treatment of chronic idiopathic constipation (70).”
BackgroundLinaclotide: A novel agent for chronic constipation and irritable bowel syndrome
Love, B. L., Johnson, A., & Smith, L. S. (2014) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp130575 · Cited by 58 · see citing works
Randomized Placebo-Controlled Phase 3 Trial of Vibrating Capsule for Chronic Constipation
Rao, S. S. C., Quigley, E. M. M., Chey, W. D., Sharma, A., & Lembo, A. J. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.02.013 · Cited by 56 · see citing works
Self-citationEmerging frontiers in drug delivery with special focus on novel techniques for targeted therapies
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Folgueira, C., Beiroa, D., Callon, A., Al–Massadi, O., Barja-Fernández, S., Senra, A., Fernø, J., López, M., Diéguez, C., Casanueva, F. F., et al. (2015) · Diabetes · doi:10.2337/db15-0889 · Cited by 56 · see citing works
“For instance, linaclotide, a synthetic peptide that is structurally related to the endogenous guanylin peptide family, activates GUCY2C and is clinically used for chronic constipation (33).”
BackgroundThe Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia
Rappaport, J. A., & Waldman, S. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00299 · Cited by 56 · see citing works
Recent advances in understanding and managing chronic constipation
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Linaclotide for the treatment of chronic constipation
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Chronic constipation: Update on management
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Irritable Bowel Syndrome: Straightening the road from the Rome criteria
Camilleri, M. (2020) · Neurogastroenterology & Motility · doi:10.1111/nmo.13957 · Cited by 49 · see citing works
Pharmacotherapy for Irritable Bowel Syndrome
Camilleri, M., & Ford, A. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6110101 · Cited by 44 · see citing works
“The increase in cGMP may also have effects on sensory afferent neurons, leading to pain inhibition, an effect noted in the phase III clinical trials of the drug that were conducted in chronic idiopathic constipation [86], where abdominal discomfort and bloating improved significantly.”
BackgroundBloating and Abdominal Distension: Clinical Approach and Management
Mari, A., Baker, F. A., Mahamid, M., Amara, H., Carter, D., Boltin, D., & Dickman, R. M. (2019) · Advances in Therapy · doi:10.1007/s12325-019-00924-7 · Cited by 48 · see citing works
Constipation: Evaluation and Management.
Jani, B. S., & Marsicano, E. V. (2018) · Europe PMC (PubMed Central) · Cited by 48 · see citing works
Mori, S., Tomita, T., Fujimura, K., Asano, H., Ogawa, T., Yamasaki, T., Kondo, T., Kono, T., Tozawa, K., Oshima, T., et al. (2019) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm18194 · Cited by 47 · see citing works
“In contrast, linaclotide induces defecation by acting on the guanylate cyclase C receptors that exist on the surface of intestinal epithelial cells and raising the concentration of cGMP in the intestinal tract to facilitate the secretion of water into the intestine.(27,28,32,39) cGMP also inhibits the afferent nerves…”
BackgroundCystine-knot peptides: emerging tools for cancer imaging and therapy
Ackerman, S. E., Currier, N. V., Bergen, J. M., & Cochran, J. R. (2014) · Expert Review of Proteomics · doi:10.1586/14789450.2014.932251 · Cited by 47 · see citing works
“Although Linaclotide has a macrocyclic structure characteristic of knottins, it is minimally absorbed through the intestinal mucosa [85].”
BackgroundShi, Y., Chen, Q., Huang, Y., Ni, L., Liu, J., Jiang, J., & Li, N. (2016) · Colorectal Disease · doi:10.1111/codi.13314 · Cited by 47 · see citing works
Evidence-Based Clinical Guidelines for Chronic Constipation 2023
Ihara, E., Manabe, N., Ohkubo, H., Ogasawara, N., Ogino, H., Kakimoto, K., Kanazawa, M., Kawahara, H., Kusano, C., Kuribayashi, S., et al. (2024) · Digestion · doi:10.1159/000540912 · Cited by 69 · see citing works
Understanding and treating refractory constipation
Bassotti, G., & Blandizzi, C. (2014) · World Journal of Gastrointestinal Pharmacology and Therapeutics · doi:10.4292/wjgpt.v5.i2.77 · Cited by 45 · see citing works
Fukudo, S., Miwa, H., Nakajima, A., Kinoshita, Y., Kosako, M., Hayashi, K., Akiho, H., Kuroishi, K., Johnston, J. M., Currie, M. G., et al. (2018) · Neurogastroenterology & Motility · doi:10.1111/nmo.13487 · Cited by 45 · see citing works
Self-citationCorsetti, M., & Tack, J. F. (2013) · United European Gastroenterology Journal · doi:10.1177/2050640612474446 · Cited by 45 · see citing works
“Hence, a substantial unmet need persists in the treatment of CC.”
MethodInfluentialFukudo, S., Endo, Y., Hongo, M., Nakajima, A., Abe, T., Kobayashi, H., Nakata, T., Nakajima, T., Sameshima, K., Kaku, K., et al. (2018) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(18)30165-1 · Cited by 50 · see citing works
Functional Constipation: Individualising Assessment and Treatment
Pannemans, J., Masuy, I., & Tack, J. (2020) · Drugs · doi:10.1007/s40265-020-01305-z · Cited by 44 · see citing works
Thomas, R. H., & Luthin, D. R. (2015) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1594 · Cited by 43 · see citing works
“Current therapeutic options include lifestyle modifications, over-the-counter (OTC) agents, antispasmodics, serotonin agonists, and lubiprostone and linaclotide, two prosecretory prescription drugs approved for the treatment of IBS-C and CIC.”
BackgroundMethodInfluentialPharmacologic, Pharmacokinetic, and Pharmacogenomic Aspects of Functional Gastrointestinal Disorders
Camilleri, M., Bueno, L. P., Andresen, V., Ponti, F. D., Choi, M., & Lembo, A. J. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.029 · Cited by 43 · see citing works
Self-citationChang, L., Chey, W. D., Imdad, A., Almario, C. V., Bharucha, A. E., Diem, S. J., Greer, K. B., Hanson, B., Harris, L. A., Ko, C. W., et al. (2023) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000002227 · Cited by 43 · see citing works
“The use of linaclotide might improve the PAC-QOL scores compared with placebo (64); however, data could not be pooled.”
BackgroundSelf-citationGuanylate Cyclase C Agonists: Emerging Gastrointestinal Therapies and Actions
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Chronic constipation and abdominal pain: Independent or closely interrelated symptoms?
Wong, M. Y. W., Hebbard, G., Gibson, P. R., & Burgell, R. (2020) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14970 · Cited by 42 · see citing works
- Authors
- Lembo, A. J., Schneier, H. A., Shiff, S. J., Kurtz, C. B., MacDougall, J. E., Jia, X. D., Shao, J. Z., Lavins, B. J., Currie, M. G., Fitch, D. A., Jeglinski, B. I., Eng, P., Fox, S. M., & Johnston, J. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Forest Laboratories (United States) (US)
- Ironwood Pharmaceuticals (United States) (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-08-11
- Volume
- 365
- Issue
- 6
- Pages
- 527-536
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2129385409
- Cited by
- 373
- References
- 18
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 28 · 2023: 22 · 2022: 19 · 2021: 23 · 2020: 23 · 2019: 20 · 2018: 31 · 2017: 24 · 2016: 32 · 2015: 26 · 2014: 26 · 2013: 40 · 2012: 25
- FWCI
- 31.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ironwood Pharmaceuticals, Incorporated
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Rheumatology › Pelvic floor disorders treatments
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- linaclotide, chronic constipation, spontaneous bowel movements, diarrhea, drug safety, treatment efficacy
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Chronic Disease, Constipation, Defecation, Diarrhea, Double-Blind Method, Female, Guanylate Cyclase, Humans, Male, Middle Aged, Peptides, Quality of Life, Withholding Treatment, Receptors, Guanylate Cyclase-Coupled, Laxatives, Young Adult
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