Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C

Michael Camilleri, Anthony J. Lembo, Bernard J. Lavins, James E. Macdougall, Robyn T. Carson, Valerie S L Williams, Lauren M. Nelson, Steven J. Shiff, Mark G. Currie, Caroline B. Kurtz, Jeffrey M. Johnston

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBSC responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively). Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

Original languageEnglish (US)
Pages (from-to)53-62
Number of pages10
JournalUnited European Gastroenterology Journal
Volume3
Issue number1
DOIs
StatePublished - 2015

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Irritable Bowel Syndrome
Constipation
Clinical Trials
Phase III Clinical Trials
Abdominal Pain
Research Personnel
linaclotide

Keywords

  • Adequate relief
  • Clinically meaningful change
  • GC-C
  • IBS-C
  • Linaclotide
  • Responder endpoints

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

Cite this

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C. / Camilleri, Michael; Lembo, Anthony J.; Lavins, Bernard J.; Macdougall, James E.; Carson, Robyn T.; Williams, Valerie S L; Nelson, Lauren M.; Shiff, Steven J.; Currie, Mark G.; Kurtz, Caroline B.; Johnston, Jeffrey M.

In: United European Gastroenterology Journal, Vol. 3, No. 1, 2015, p. 53-62.

Research output: Contribution to journalArticle

Camilleri, M, Lembo, AJ, Lavins, BJ, Macdougall, JE, Carson, RT, Williams, VSL, Nelson, LM, Shiff, SJ, Currie, MG, Kurtz, CB & Johnston, JM 2015, 'Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C', United European Gastroenterology Journal, vol. 3, no. 1, pp. 53-62. https://doi.org/10.1177/2050640614555946
Camilleri, Michael ; Lembo, Anthony J. ; Lavins, Bernard J. ; Macdougall, James E. ; Carson, Robyn T. ; Williams, Valerie S L ; Nelson, Lauren M. ; Shiff, Steven J. ; Currie, Mark G. ; Kurtz, Caroline B. ; Johnston, Jeffrey M. / Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C. In: United European Gastroenterology Journal. 2015 ; Vol. 3, No. 1. pp. 53-62.
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AU - Macdougall, James E.

AU - Carson, Robyn T.

AU - Williams, Valerie S L

AU - Nelson, Lauren M.

AU - Shiff, Steven J.

AU - Currie, Mark G.

AU - Kurtz, Caroline B.

AU - Johnston, Jeffrey M.

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N2 - Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBSC responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively). Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

AB - Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBSC responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively). Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

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KW - Responder endpoints

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