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#189 Moving along the management of constipation predominant IBS – Is it worth the cost?

What is the efficacy and safety of linaclotide in constipation predominant irritable bowel syndrome (IBS-C)?

Compared to placebo, for every seven patients treated with linaclotide one more will be a “responder” [30% improvement in pain and one additional complete spontaneous bowel movement (CSBM) per week for six weeks in 12]Overall, patients experience ~3 additional “spontaneous” bowel movements (BM) per week, at the price of $15 per BMFor every 21 patients treated, one will stop due to diarrhea. Post-marketing surveillance should help clarify long-term safety.  

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  • Two multicentre, Randomized Controlled Trials (RCTs) (803 and 805 patients)1,2 comparing linaclotide 290 mcg to placebo in IBS-Cand three systematic reviews.3-5 
    • Both RCTs had strikingly similar baseline demographics and outcomes at 12 weeks:1,2 
      • Mean age 44~ 90% female, ~78Caucasian. 
      • Baseline abdominal pain ~5.6 on 0-10 point scale, CSBM 0.2/week. 
    • Primary outcome 
      • “Responder”: 30% reduction in abdominal pain and increase of one CSBM per week for six of the 12 weeks.1,2  
      • 34% linaclotide versus 14-21% placebo.1,2 
      • Combined number needed to treat=7.3,4   
    • Secondary outcomes: 
      • ~3 additional spontaneous BM per week (above placebo).1,2 
      • Average pain reduction in both trials was 1.9 linaclotide versus 1.1 placebo (0-10 scale). 
        • Minimally clinically important difference=2.2.6 
    • Adverse outcomes: 
      • Diarrhea resulting in discontinuation:1,2  
        • 4-6linaclotide versu0.2-0.3% placebo.  
        • Combined Number Needed to Harm=21. 
    • Limitations: Unclear recruitmentrun in excluded >40% of patients.  
    • Over 40 publication(abstract and peer-reviewed) on two RCTs with common author (employee of linaclotide manufacturer)Some inconsistent data between abstracts and peer-reviewed publications.3,7  
  • One smaller RCT reported similar outcomes.8 
  • Publication bias likely: Two open-label, 52 and 78-week safety studies with 1,557 and 1,743 patients completed in 2012 and 2013 not fully published9-11 but have been evaluated by the FDA.12  
  • At least two other IBS-C drugs have been withdrawn due to safety concerns:  
    • Tegaserod5-HT4 antagonist due cardiovascular risk.13  
    • Alosetron: 5-HT3 antagonist due to ischemic colitis.14  
  • Linoclotide costs approximately $180 per month or ~$15 per additional BM. 

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  • Brent Turner MD
  • Christina Korownyk MD CCFP
  • Michael R Kolber BSc MD CCFP MSc

1. Rao S, Lembo AJ, Shiff SJ, et al. Am J Gastroenterol. 2012; 107(11):1714-24.

2. Chey WD, Lembo AJ, Lavins BJ, et al. Am J Gastroenterol. 2012; 107(11):1702-12.

3. Atluri DK, Chandar AK, Bharucha AE, et al. Neurogastroenterol Motil. 2014 Apr; 26(4):499-509.

4. Videlock EJ, Cheng V, Cremonini F. Clin Gastroenterol Hepatol. 2013 Sep; 11(9):1084-92.e3.

5. Ford AC, Moayyedi P, Lacy BE, et al. Am J Gastroenterol. 2014 Aug; 109 Suppl 1:S2-26.

6. Spiegel B, Bolus R, Harris LA, et al. Aliment Pharmacol Ther. 2009; 30(11-12):1159-70.

7. Chey WD, Lembo A, MacDougall JE, et al. [Abstract] Gastroenterol. 2011;140(5):S-135.

8. Johnston JM, Kurtz CB, Macdougall JE, et al. Gastroenterol. 2010; 139(6):1877-86.e2.

9. Diaz C, Falques M, Vilardell D, et al. [Abstract] Gut. 2015; 64(Suppl 1):A144.2-A145.

10. Chey W, Shiff S, Schneier H, et al. [Abstract] Am J Gastroenterol. 2014; 109:S527-S544.

11. [internet]. NCT00765999 and NCT00730171. Available at Last accessed: March 1, 2017.

12. Center for Drug Evaluation and Research [internet]. Available at: Last accessed: March 7, 2017.

13. Federal Drug Administration [intenet]. August 27, 2013. Available at: Last accessed: March 1, 2017.

14. Weinberg DS, Smalley W, Heidelbaugh JJ, et al. Gastroenterol. 2014; 147:1146-8.

Authors do not have any conflicts of interest to declare.