Less Small-Bowel Injury With Lumiracoxib Compared With Naproxen Plus Omeprazole

doi:10.1016/j.cgh.2007.12.023

Clinical Gastroenterology and Hepatology

Volume 6, Issue 5, May 2008, Pages 536-544

https://doi.org/10.1016/j.cgh.2007.12.023 Get rights and content

Background & Aims: The selective cyclooxygenase-2 inhibitor lumiracoxib has been shown to reduce endoscopically detected ulcers and ulcer complications in the upper gastrointestinal tract compared with nonselective nonsteroidal anti-inflammatory drugs. We investigated whether lumiracoxib would reduce small-bowel injury compared with naproxen plus omeprazole. Methods: Healthy volunteers were randomized to receive lumiracoxib 100 mg once daily, naproxen 500 mg twice daily plus omeprazole 20 mg once daily, or placebo in a 16-day double-blind, parallel-group study. Small-bowel mucosal injury and inflammation were assessed by video capsule endoscopy, the lactulose:L-rhamnose permeability assessment, and the fecal calprotectin test. Results: Of 152 randomized subjects, 139 completed the study with valid video capsule endoscopies (lumiracoxib, n = 47; naproxen plus omeprazole, n = 45; placebo, n = 47). Compared with placebo, an increased number of subjects on naproxen plus omeprazole had small-bowel mucosal breaks (77.8% vs 40.4%, P < .001), with increased permeability (P = .023) and increased fecal calprotectin (increase, 96.8 vs 14.5 mg/kg for placebo; P < .001). With lumiracoxib, 27.7% of subjects had small-bowel mucosal breaks (P = .196 vs placebo; P < .001 vs naproxen), there was no increase in permeability (P = .157 vs placebo; P = .364 vs naproxen), and no increase in fecal calprotectin (–5.7 mg/kg; P = .377 vs placebo; P < .001 vs naproxen). Conclusions: As assessed by 3 different measures, acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.

Section snippets

Study Design

This was a 16-day, randomized, double-blind, double-dummy, placebo-controlled, parallel-group trial comparing lumiracoxib 100 mg once a day (the recommended dose in osteoarthritis) with naproxen 500 mg twice a day plus omeprazole 20 mg once a day and with placebo in healthy volunteers to confirm the safety and tolerability of lumiracoxib in the small bowel. The study was conducted in 2 centers in Germany and in 1 center in the United Kingdom. Each study center received ethics committee approval

Results

Of the 259 subjects screened, 107 subjects were screen failures, including 62 subjects with mucosal breaks/lesions in their small bowel as detected by VCE. The remaining 152 subjects were randomized (lumiracoxib, 52; naproxen plus omeprazole, 50; and placebo, 50) and 139 subjects (lumiracoxib, 47; naproxen plus omeprazole, 45; and placebo, 47) completed at least 13 days of study treatment and had valid end-of-study VCEs (primary analysis population).

Baseline demographic and background

Discussion

In this study we evaluated small-bowel mucosal injury and inflammation by 3 discrete methods. Each of these methods has shown an increase in the index of small-bowel injury/inflammation in subjects treated with naproxen plus omeprazole compared with placebo. In contrast, in subjects receiving lumiracoxib, levels of mucosal injury or inflammation did not differ significantly from placebo and were reduced significantly compared with naproxen plus omeprazole on 2 of 3 measures. On lumiracoxib,

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The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enteropathy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo.
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Citation Excerpt :
This post-hoc analysis however did not stratify by use of the NSAID that patients were randomized to (celecoxib or diclofenac plus omeprazole) [18c]. However, results from other studies evaluating lower GI tract events as an outcome were conflicting [16c, 19c, 20c, 21c]. A post-hoc analysis of a prospective study showed a lower rate of serious lower GI events for rofecoxib compared to naproxen [16c], whereas this was not confirmed in a cross-sectional capsule enteroscopy study showing comparable small-bowel damage between long-term NSAID and coxib users [20c].
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: The study and statistical analyses were funded by Novartis Pharma AG. Christopher Hawkey has received research funding and/or honoraria from AstraZeneca, Bayer, Takeda, MerckSerono, and Novartis; Jörg Albert, Martin Keuchel, and Mark McAlindon acted as paid consultants on the panel grading the injuries shown on the capsule endoscopy videos; Vincent Yu is an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; Udayasankar Arulmani, Gerhard Krammer, and Rosemary Rebuli are employees of, and own shares in, Novartis Pharma AG, Basel, Switzerland.

: Novartis funded the study, and both Novartis and the lead investigators were involved in the study design. Novartis and the external authors were involved in the collection, analysis, and interpretation of the data, as well as in the writing of the report and in the decision to submit the paper for publication.

: The first draft of the article was written by the first listed author, with all authors then contributing.

: The authors would like to thank Dr. Graham Allcock, a professional medical writer with ACUMED, for his assistance in the preparation of the manuscript, consolidating comments, and incorporating subsequent revisions. His role was funded by Novartis. The authors thank the staff of the centers involved in this work, the clinical trial team for their expert collaboration, and the subjects who participated in the study.

: Ervin Toth was the Central Reader and the adjudication committee comprised Jörg Albert, Martin Keuchel, and Mark McAlindon.

: Potential conflicts of interest were not disclosed to study participants.

View full text

Original article—alimentary tractLess Small-Bowel Injury With Lumiracoxib Compared With Naproxen Plus Omeprazole

Section snippets

Study Design

Results

Discussion

Lancet

Best Pract Res Clin Gastroenterol

Clin Gastroenterol Hepatol

Lancet

J Am Coll Surg

Clin Gastroenterol Hepatol

Lancet

Gastroenterology

Clin Gastroenterol Hepatol

Clin Ther

Lancet

Clin Ther

Gastrointest Endosc

Gastroenterology

Gastroenterology

Lancet

Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man

Gut

COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin

Gut

Intestinal permeability and inflammation in patients on NSAIDs

Gut

Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs

N Engl J Med

Nonsteroidal antiinflammatory drugs and the small intestine

Curr Opin Gastroenterol

Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood lossEffects of sulfasalazine and other disease-modifying antirheumatic drugs

Arthritis Rheum

Colonic strictures induced by nonsteroidal anti-inflammatory drugs

South Med J

Non-steroidal anti-inflammatory drugs: overall risks and managementComplementary roles for COX-2 inhibitors and proton pump inhibitors

Gut

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trialCelecoxib Long-term Arthritis Safety Study

JAMA

Original article—alimentary tract
Less Small-Bowel Injury With Lumiracoxib Compared With Naproxen Plus Omeprazole