Efficacy and Safety of Lubiprostone in the Treatment of Slow Transit Constipation

Official title

Efficacy and Safety of Lubiprostone in the Treatment of Slow Transit Constipation: A Multicenter, Randomized Controlled Trial

Overview

Lubiprostone has established efficacy and a favorable safety profile in chronic constipation and irritable bowel syndrome with constipation (IBS-C). However, clinical data specifically supporting its use in slow-transit constipation (STC), a distinct subtype of chronic constipation, remains limited.

Detailed description

Slow-transit constipation (STC) is a common subtype of chronic constipation, accounting for up to 30% of cases. Its clinical hallmarks include a diminished or absent urge to defecate and a significantly reduced stool frequency (spontaneous bowel movements \<3 per week). The condition often follows a prolonged and progressively worsening course, characterized by straining, passage of hard stools, and associated symptoms such as abdominal pain and bloating. In severe cases, fecal impaction and consequent colonic obstruction may occur, substantially impairing the patient's quality of life.

Non-surgical management, including lifestyle modifications, pharmacological therapy, gut microbiome modulation, and sacral nerve stimulation, remains the first-line approach for most STC patients. Among these, pharmacotherapy is central. Conventional agents include bulk-forming, osmotic, and stimulant laxatives, as well as prokinetics. However, these options are often limited by adverse effects-such as abdominal pain, bloating, rash, drug dependence, malabsorption, and electrolyte imbalances-and the development of tolerance with long-term use. This frequently leaves patients with inadequate relief, creating an urgent need for more effective and safer therapeutics.

Lubiprostone, a chloride channel activator that functions as a secretagogue, enhances intestinal fluid secretion and motility. Its efficacy and safety in chronic idiopathic constipation and irritable bowel syndrome with constipation are well-documented, leading to approvals by the U.S. FDA for these indications. Nevertheless, specific data on its use for STC, a distinct pathophysiological entity, is lacking. This study is therefore designed to evaluate the clinical efficacy and safety of lubiprostone in an STC population, with the aim of generating new evidence to inform precise treatment strategies for this condition.

Interventions

• Drug Lubiprostone
  Patients were instructed to orally ingest Lubiprostone Soft Capsules (provided by Nanjing Chia-Tai Tianqing Pharmaceutical Company) at a dose of 24 μg twice daily with food and water during breakfast and dinner. The capsules must be swallowed whole without splitting or chewing. The treatment duration was 4 weeks, and medication adherence was monitored through patient diaries and pill count of returned medication.
• Drug Polyethylene glycol (PEG )
  Subjects in the control group will receive the standard treatment of polyethylene glycol 4000 powder at a dosage of 10 g, twice daily. Each dose will be dissolved in 200-250 mL of water and administered orally for 4 weeks.

Primary outcome measures

• The change in spontaneous bowel movements (SBMs) frequency from baseline during the first week [Time frame: From 2 weeks prior to the first dose through 4 weeks after treatment initiation]

Secondary outcome measures (11)

• The percentage of patients with SBMs within 24 hours after the first intake of the study drug [Time frame: Day 1 after treatment initiation]
• Time to first SBM occurrence after treatment initiation [Time frame: Up to 4 weeks after treatment initiation]
• The percentage of patients reporting 3 or more SBMs/wk [Time frame: From 2 weeks prior to the first dose through 4 weeks after treatment initiation]
• The percentage of patients achieving an increase of ≥1 SBMs/week from baseline [Time frame: From 2 weeks prior to the first dose through 4 weeks after treatment initiation]
• The change from baseline in the weekly average number of SBMs at weeks 2, 3, and 4 [Time frame: From 2 weeks prior to the first dose through 4 weeks after treatment initiation]
• The change from baseline in the Bristol Stool Form Scale (BSFS) values for SBMs at weeks 1 and 4 [Time frame: The 1 and 4-week treatment period has been completed]
• The change from baseline in the ratings of straining associated with SBMs at weeks 1 and 4 [Time frame: The 1 and 4-week treatment period has been completed]
• The change from baseline in the Wexner constipation score at weeks 1 and 4 [Time frame: The 1 and 4-week treatment period has been completed]
• The change from baseline in the Patient Assessment of Constipation Quality of Life (PAC-QOL) score at weeks 1 and 4 [Time frame: The 1 and 4-week treatment period has been completed]
• The patients' satisfaction scores at weeks 1 and 4 [Time frame: The 1 and 4-week treatment period has been completed]
• The rate of adverse reactions, including nausea, diarrhea, and abdominal pain. [Time frame: Up to 4 weeks after treatment initiation]

Eligibility criteria

Inclusion criteria

• Patients voluntarily participated in the study and provided signed informed consent;
• Met the Rome IV diagnostic criteria for functional constipation;
• Had fewer than 3 spontaneous bowel movements (SBMs) per week;
• More than 20% the radio-paque markers localized in the colon after 72 hours based on colonic transit studies;
• Were able to complete the bowel movement diary and study questionnaires as required by the study protocol;
• Agreed to use effective contraception from the time of signing the informed consent form until 3 months after the last dose of the study drug;
• Aged 18 years or older, both males and females.

Exclusion criteria

• Pregnant or lactating women.
• Patients with severe outlet obstruction constipation (e.g. Oxford Grade IV or above for rectal prolapse, rectocele > 3.1 cm, puborectalis syndrome).
• Patients with hyperthyroidism or hypothyroidism.
• Patients with opioid-induced constipation.
• Patients with megacolon or megarectum.
• Patients with apparent mechanical intestinal obstruction.
• Patients with inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis).
• Patients with malignant tumors of the digestive system.
• Patients with a history of colorectal surgery.
• Patients with a previous history of taking lubiprostone.
• Patients with severe symptoms of depression or anxiety.
• Patients with known or suspected hypersensitivity to lubiprostone/polyethylene glycol 4000 or any excipients.
• Patients requiring medications for Parkinson's disease, antipsychotics, antimanic agents, or psychostimulants.
• Patients with severe cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematologic, neurological, or psychiatric diseases.
• Other patients deemed by the investigator as unsuitable for participation in this trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 20 centers

• Bishan Hospital of Chongqing — Bishan
• the People's Hospital of HeChuan Chongqing — Hechuan
• Shapingba District Traditional Chinese Medicine Hospital in Chongqing — Shapingba
• Shapingba Hospital, Chongqing University — Shapingba
• The Chenjiaqiao Hospital of ShaPingba District of Chongqing — Shapingba
• Army Medical Center (Daping Hospital) — Yuzhong
• Gansu Province Central Hospital — Lanzhou
• The First Hospital of Hebei Medical University — Shijiazhuang
• … and 12 more centers

Publications

• Cinca R, Chera D, Gruss HJ, Halphen M. Randomised clinical trial: macrogol/PEG 3350+electrolytes versus prucalopride in the treatment of chronic constipation -- a comparison in a controlled environment. Aliment Pharmacol Ther. 2013 May;37(9):876-86. doi: 10.1111/apt.12278. Epub 2013 Mar 11. PMID 23480216
• Chang L, Chey WD, Imdad A, Almario CV, Bharucha AE, Diem S, Greer KB, Hanson B, Harris LA, Ko C, Murad MH, Patel A, Shah ED, Lembo AJ, Sultan S. American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation. Gastroenterology. 2023 Jun;164(7):1086-1106. doi: 10.1053/j.gastro.2023.03.214. PMID 37211380
• Christie J, Shroff S, Shahnavaz N, Carter LA, Harrison MS, Dietz-Lindo KA, Hanfelt J, Srinivasan S. A Randomized, Double-Blind, Placebo-Controlled Trial to Examine the Effectiveness of Lubiprostone on Constipation Symptoms and Colon Transit Time in Diabetic Patients. Am J Gastroenterol. 2017 Feb;112(2):356-364. doi: 10.1038/ajg.2016.531. Epub 2016 Dec 6. PMID 27922028
• Li F, Fu T, Tong WD, Liu BH, Li CX, Gao Y, Wu JS, Wang XF, Zhang AP. Lubiprostone Is Effective in the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Mayo Clin Proc. 2016 Apr;91(4):456-68. doi: 10.1016/j.mayocp.2016.01.015. PMID 27046523
• Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. Am J Gastroenterol. 2015 May;110(5):725-32. doi: 10.1038/ajg.2015.106. Epub 2015 Apr 28. PMID 25916220
• Ondo WG, Kenney C, Sullivan K, Davidson A, Hunter C, Jahan I, McCombs A, Miller A, Zesiewicz TA. Placebo-controlled trial of lubiprostone for constipation associated with Parkinson disease. Neurology. 2012 May 22;78(21):1650-4. doi: 10.1212/WNL.0b013e3182574f28. Epub 2012 May 9. PMID 22573627
• Chey WD, Drossman DA, Johanson JF, Scott C, Panas RM, Ueno R. Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2012 Mar;35(5):587-99. doi: 10.1111/j.1365-2036.2011.04983.x. Epub 2012 Jan 18. PMID 22251419
• Carter NJ, Scott LJ. Lubiprostone: in constipation-predominant irritable bowel syndrome. Drugs. 2009 Jun 18;69(9):1229-37. doi: 10.2165/00003495-200969090-00007. PMID 19537839

Identifiers

NCT: NCT07277907 · LB20250919 · 82370547

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗