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Original Contribution |

Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease:  The EPIC Randomized Controlled Trials FREE

Brian G. Feagan, MD; William J. Sandborn, MD; Ulrich Mittmann, MD; Simon Bar-Meir, MD; Geert D’Haens, MD, PhD; Marc Bradette, MD; Albert Cohen, MD; Chrystian Dallaire, MD; Terry P. Ponich, MD; John W. D. McDonald, MD, PhD; Xavier Hébuterne, MD, PhD; Pierre Paré, MD; Pavel Klvana, MD; Yaron Niv, MD; Sandro Ardizzone, MD; Olga Alexeeva, MD; Alaa Rostom, MD; Gediminas Kiudelis, MD; Johannes Spleiss, MSc; Denise Gilgen, PhD; Margaret K. Vandervoort, MSc; Cindy J. Wong, MSc; Guang Yong Zou, PhD; Allan Donner, PhD; Paul Rutgeerts, MD, PhD
[+] Author Affiliations

Author Affiliations: Robarts Clinical Trials, Robarts Research Institute (Drs Feagan, Zou, and Donner and Mss Vandervoort and Wong) and Department of Epidemiology and Biostatistics (Drs Feagan, Zou, and Donner), University of Western Ontario, London, Ontario, Canada; Mayo Clinic, Rochester, Minnesota (Dr Sandborn); MP Consulting, Basel, Switzerland (Dr Mittmann); Sheba Medical Center, Tel Hashomer, Israel (Dr Bar-Meir); Imelda General Hospital, Imeldalaan Bonheiden, Belgium (Dr D’Haens); Pavillon Hôtel-Dieu de Québec, Québec City, Québec, Canada (Dr Bradette); Jewish General Hospital, Montreal, Québec, Canada (Dr Cohen); Pavillon Saint-François d’Assise, Québec City (Dr Dallaire); London Health Sciences Centre, London, Ontario, Canada (Drs Ponich and McDonald); Centre Hospitalier Universitaire, University of Nice Sophia Antipolis, Nice, France (Dr Hébuterne); Hôpital Saint-Sacrement, Québec City (Dr Paré); University Hospital, Ostrava, Czech Republic (Dr Klvana); Rabin Medical Center, Petah Tiqva, Israel (Dr Niv); Ospedale Luigi Sacco, Milan, Italy (Dr Ardizzone); Regional Clinical Hospital, Nizhny Novgorod, Russia (Dr Alexeeva); University of Calgary, Calgary, Alberta, Canada (Dr Rostom); Kaunas Medical University, Kaunas, Lithuania (Dr Kiudelis); Tillotts Pharma AG, Ziefen, Switzerland (Mr Spleiss and Dr Gilgen); and University Hospital Gasthuisberg, Herestraat, Leuven, Belgium (Dr Rutgeerts).


JAMA. 2008;299(14):1690-1697. doi:10.1001/jama.299.14.1690.
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Published online

Context Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority.

Objective To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease.

Design, Setting, and Patients Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively.

Interventions Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted.

Main Outcome Measure Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease.

Results For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease.

Conclusion In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease.

Trial Registration clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542

Figures in this Article

Effective therapy to maintain remission in Crohn disease is an unmet medical need. Although formulations of 5-aminosalicylic acid agents remain widely used for this purpose, strong evidence exists that they are not effective.1 Immunosuppressive agents such as purine antimetabolites,2,3 methotrexate,4 and tumor necrosis factor α antagonists58 are moderately effective for maintaining remission; however, their use is associated with an increased risk of infection.911 Therefore, development of a safe, inexpensive, and effective orally administered agent is a research priority.

Omega-3 free fatty acids are anti-inflammatory substances found in marine fish that have several health benefits. These compounds have been used to treat inflammatory disorders such as rheumatoid arthritis12,13 and IgA nephropathy.14 Additionally, administration of omega-3 free fatty acids reduces the concentration of serum triglycerides in patients with dyslipidemia1517 and decreases the risk of death from cardiac disease.1820 However, previous clinical trials that evaluated omega-3 free fatty acids for maintenance of remission in Crohn disease have yielded inconsistent results. Belluzzi et al21 demonstrated a 33% absolute reduction in the 1-year risk of relapse in patients treated with 2.7 g/d of omega-3 free fatty acids compared with placebo. In contrast, no benefit was observed in a second trial in which patients received 5 g/d of highly concentrated omega-3 free fatty acids.22 Based on these observations, we conducted 2 large-scale trials of high-dose omega-3 free fatty acids as maintenance therapy in patients with quiescent Crohn disease. Two independent trials were performed, in complementary populations of patients, to meet regulatory expectations.

These multicenter, randomized, double-blind, placebo-controlled studies were conducted in Canada, Europe, Israel, and the United States between January 2003 and February 2007. Fifty-one sites participated in Epanova Program in Crohn's Study 1 (EPIC-1), and 47 sites participated in EPIC-2. The institutional review board at each site approved the protocols. All patients provided written informed consent.

Eligible patients were adults with a confirmed diagnosis of Crohn disease and a Crohn's Disease Activity Index (CDAI)23 score of less than 150 points. In EPIC-1, patients were eligible if they had experienced a disease exacerbation within the past year and were in remission for at least 3 months but not longer than 12 months. In EPIC-2, patients with active disease were treated with a standardized 16-week tapering course of either prednisone24 or budesonide25 at initial doses of 40 mg once daily and 9 mg once daily, respectively. Eight weeks after the initiation of corticosteroid treatment, the CDAI score was assessed; if it was less than 150 points, the patient was eligible for randomization. At this time, patients were receiving either 20 mg/d of prednisone or 6 mg/d of budesonide.

Patients were not eligible if they were allergic or intolerant of omega-3 free fatty acids or fish products; if they required treatment with 5-aminosalicylates, immunosuppressives, tumor necrosis factor α antagonists, or investigational drugs; had an ostomy or short bowel syndrome; or if they had a bowel resection in the preceding 3 months or had clinically important bowel obstruction (defined by the presence of proximal dilatation demonstrated radiographically) in the 3 months prior to randomization. Patients with malignancy (with the exception of resected basal or squamous cell skin cancer or carcinoma of the cervix in situ), those with substance abuse, or those with severe medical diseases other than Crohn disease were not included.

Study Design

Eligible patients were randomly assigned, in a 1:1 ratio using a random number generator, to receive four 1-g gelatin capsules of omega-3 free fatty acids (Epanova; Tillotts Pharma AG, Ziefen, Switzerland) or 4 capsules of identical-appearing placebo each day for 52 weeks in EPIC-1 or for 58 weeks in EPIC-2. Epanova consists of 50% to 60% eicosapentanonic acid and 15% to 25% docosahexanoic acid as a free fatty acid encapsulated in a delayed-release soft gelatin capsule. The placebo capsule consisted of 1 g of medium-chain triglyceride oil. To enhance tolerability, patients began with an initial dose of 1 g/d of the study drug for the first 7 days; this was increased to 2 g/d daily for 7 days and then further increased to the final dose of 4 g/d, administered as 2 capsules twice daily.

Both studies used a central randomization procedure that was stratified by the induction therapy received prior to randomization or the duration of remission (For EPIC-1: 5-aminosalicylates; corticosteroids and in remission for 3 to 6 months; corticosteroids and in remission for 6 to 12 months; or immunosuppressives. For EPIC-2: prednisone or budesonide for induction therapy). Neither the investigators nor the patients were aware of the treatment assignment.

No new medications for Crohn disease were allowed following randomization. Participants in EPIC-2 had the dose of corticosteroid tapered. Those receiving budesonide decreased the daily dose to 3 mg by week 4, with discontinuation at week 8. Patients receiving prednisone decreased the daily dose by 2.5 mg/wk, with discontinuation at week 8. An increase in the dose of corticosteroid to control symptoms was considered a failure of treatment.

Follow-up Schedule

Patients were evaluated in the clinic at weeks −1, 0 (randomization), 4, 16, 30, 44, and 52 for EPIC-1 and at weeks −8, 0 (randomization), 2, 8, 16, 30, 44, and 58 for EPIC-2. At each visit patients were given a physical examination, blood was drawn for biochemical testing, and results of the CDAI and 36-Item Short-Form Health Survey (SF-36)26 were assessed.

Outcome Measures

The primary efficacy outcome was the occurrence of a relapse, defined as either an increase of the CDAI score to 150 points or greater and an increase of more than 70 points from the score calculated at the randomization visit, or the initiation of prohibited medical therapy or surgery for symptomatic active Crohn disease.4 Secondary outcomes were the change in mean scores on the CDAI and SF-36, the change in the mean serum triglyceride concentration, and the occurrence of adverse events, which were classified using the Medical Dictionary for Regulatory Activities.27

Adherence to the study drug as assigned was evaluated at each clinic visit by interviewing the patient and by capsule counts. Patients were considered adherent if they received at least 75% of the capsules between 2 clinic visits, with no interruption of medication for more than 14 consecutive days.

Statistical Analysis

Baseline characteristics were analyzed using the t test or the χ2 test as appropriate. For the primary analysis the time to a relapse was compared by treatment group using the log-rank test. Kaplan-Meier plots were used to depict the proportion of patients remaining in remission over time. Hazard ratios (HRs) and associated confidence intervals (CIs) were obtained using Cox regression with treatment assignment as the only independent variable. For EPIC-1, a prespecified subgroup analysis was also conducted to evaluate the primary outcome in patients whose remission had been induced by corticosteroids. A Bonferroni correction (P ≤.025) was applied for this comparison. The mean changes in CDAI, SF-36 scores, and serum triglyceride concentrations were compared by the t test. Point estimates and 95% CIs of the between-group difference in the proportion of patients with adverse events were obtained. The proportion of patients compliant with the study drug was compared using the χ2 test.

All analyses were performed according to a modified intent-to-treat principle in which data from all patients who received at least 1 dose of the study drug and who provided any postrandomization data were analyzed. A 2-sided P value less than .05 was considered statistically significant. SAS version 8.228 was used to perform these analyses; however, CIs were estimated using StatXact version 8.0.29

Both trials were designed to detect a 15%30 reduction in relapse rate with 80% power at the .05 significance level. We estimated that the relapse rate in the placebo group would be 70% in EPIC-1.21 For EPIC-2, we estimated that 80% of the patients would achieve clinical remission at the discontinuation of corticosteroid induction therapy and that the rate of relapse in the patients who were subsequently assigned to placebo would be 80%.31 Accordingly, a total of 306 patients and 309 patients were required to detect an absolute difference of 15% in the relapse rate for EPIC-1 and EPIC-2, respectively. We planned to randomize 360 patients in EPIC-1 and 364 patients in EPIC-2 to allow for a nonevaluable rate of 15%.

The disposition of the patients is shown in Figure 1. In EPIC-1, 383 patients were randomized. During the conduct of EPIC-1, it was discovered that a single site had not conducted the trial according to International Conference on Harmonisation E6 guidelines32 and had not followed the protocol on numerous occasions. Following consultation with regulatory agencies, all of the data collected on the 9 patients randomized from this site were excluded from analysis. Of the remaining 374 patients, 2 did not receive study drug, 8 had no postrandomization relapse assessment, and 1 was rerandomized in error. Thus, a total of 363 patients were included in the modified intent-to-treat population; of these, 183 received omega-3 free fatty acids and 180 received placebo. In EPIC-2, 379 patients were randomized, 2 did not receive study drug, and 2 had no postrandomization assessment. Thus, a total of 375 patients were included in the modified intent-to-treat population; of these, 187 received omega-3 free fatty acids and 188 received placebo.

Place holder to copy figure label and caption
Figure 1. Disposition of Patients During the Conduct of EPIC-1 and EPIC-2
Graphic Jump Location

EPIC indicates Epanova Program in Crohn’s Study.

In EPIC-1, 26 patients who did not experience relapse discontinued treatment prematurely in the omega-3 free fatty acids group compared with 29 in the placebo group (P = .61). In EPIC-2, 30 patients who did not experience relapse discontinued treatment prematurely in the omega-3 free fatty acids group compared with 18 in the placebo group (P = .06). No important differences were observed between the treatment groups in the reasons for withdrawal in either trial (Figure 1).

The baseline characteristics of the patients were similar for both treatment groups in each trial (Table 1).33

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Patients in EPIC-1 and EPIC-2a
Primary Outcome

Figure 2 shows the proportion of patients who remained in remission over time. No significant differences were observed between the 2 treatment groups in either trial. In EPIC-1, 54 patients treated with omega-3 free fatty acids and 62 patients treated with placebo experienced a clinical relapse. The proportion of patients assigned to receive omega-3 free fatty acids who experienced a relapse within 360 days was estimated to be 31.6%, compared with 35.7% for those who received placebo (HR, 0.82; 95% CI, 0.57-1.19; P = .30). In EPIC-2, 84 patients treated with omega-3 free fatty acids and 94 patients treated with placebo experienced a clinical relapse. The proportion of patients assigned to receive omega-3 free fatty acids who experienced a relapse within 360 days was estimated to be 47.8%, compared with 48.8% of those who received placebo (HR, 0.90; 95% CI, 0.67-1.21; P = .48).

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Estimates of the Time to Relapse in the Omega-3 Free Fatty Acids and Placebo Groups for EPIC-1 and EPIC-2
Graphic Jump Location

EPIC indicates Epanova Program in Crohn’s Study.

In the subgroup of patients in EPIC-1 who had received induction therapy with corticosteroids, no significant difference was observed between the 2 treatment groups. Thirty-eight percent of those who received omega-3 free fatty acids experienced a relapse at 360 days compared with 39.5% in the placebo group (P = .60).

Disease Activity and Quality of Life

No important differences were observed in the changes in mean CDAI and SF-36 scores in either study (data not shown).

Adherence to Study Drug

In EPIC-1, 79.2% of patients who received omega-3 free fatty acids had adequate adherence to study drug, compared with 75.6% of those who received placebo (P = .40). The corresponding values for EPIC-2 were 75.4% and 81.4%, respectively (P = .16).

Serum Triglycerides

A significant decrease in serum triglyceride concentration was observed in patients assigned to receive omega-3 free fatty acids. In EPIC-1, the mean decrease after 30 weeks of treatment was −21.5 mg/dL (to convert to millimoles per liter, multiply by 0.0113), compared with a mean increase of 16.5 mg/dL in patients who received placebo (P < .001). Corresponding values for EPIC-2 were −27.1 mg/dL in patients treated with omega-3 free fatty acids, compared with −5.1 mg/dL in patients receiving placebo (P = .02).

Adverse Events

No important differences were observed between the treatment groups in the incidence of adverse events (Table 2). The overall frequency of adverse events was higher in EPIC-2 because these patients had active disease at the time of entry and were receiving treatment with corticosteroids. The omega-3 free fatty acid formulation was well tolerated, and previously observed adverse events such as diarrhea and bloating21 were uncommon. No differences in laboratory results were identified apart from the reduced triglyceride concentration observed in patients who received omega-3 free fatty acids.

Table Graphic Jump LocationTable 2. Incidence of Adverse Events, EPIC-1 and EPIC-2a

These 2 large-scale trials had similar results. No beneficial effect of high-dose omega-3 free fatty acid treatment was observed for the prevention of relapse over 1 year of follow-up. These findings are distinctly different from those of Belluzzi at al,21 who reported a 33% absolute reduction in the rate of relapse following treatment with a similar omega-3 free fatty acid formulation in a randomized placebo-controlled trial that evaluated 78 patients.

There are 3 possible explanations for these discordant results. First, the design of the study by Belluzzi et al21 differed from the EPIC trials in that only patients at a high risk of relapse, defined by the presence of an elevated serum concentration of acute-phase reactants, were included. It could be speculated that the patients evaluated in the EPIC studies were at such low risk that the trials lacked sufficient statistical power to detect the prespecified 15% benefit of treatment. While this hypothesis might be plausible in the case of EPIC-1, given that the 1-year placebo relapse rate was only 35.7%, it is not tenable for EPIC-2, in which 51.2% of patients relapsed. Furthermore, our results are consistent with those of Lorenz-Meyer et al,22 who also demonstrated no benefit of omega-3 fatty acids in a placebo-controlled relapse prevention study that evaluated 204 patients.

A second possible explanation concerns the different formulations used in the studies. The formulation evaluated in the study by Belluzzi et al was a hard gelatin capsule, in contrast to the soft gelatin capsule used in the current trials. However, pharmacokinetic studies have shown that a similar concentration of omega-3 free fatty acids is incorporated into cell membranes following administration of either preparation (J.S., written communication, January 2004, data on file). Moreover, although no beneficial effect was observed for the prevention of relapse, a statistically significant decrease in the serum concentration of triglycerides was observed in patients who received omega-3 free fatty acids. This finding, which is consistent with our analysis of the capsule counts, indicates the patients had adequate exposure to the study drug and that poor compliance cannot account for the negative results.

Finally, we believe that the most plausible explanation for the discordant findings is that the study by Belluzzi et al, which only evaluated 78 patients, was incorrect in concluding that treatment with omega-3 free fatty acids is beneficial. Several studies have demonstrated that small clinical trials are more susceptible to bias, are often less methodologically rigorous, and produce relatively less precise estimates of the true effect of treatment than large, multicenter studies.3436

Our results are important because the use of alternative medicines in general, and omega-3 free fatty acid formulations in particular, is widespread among patients with inflammatory bowel disease.3741 This may be due, in part, to dissemination of the positive results obtained in the trial by Belluzzi et al. Given the negative results observed in the EPIC trials and in the trial by Lorenz-Meyer et al,22 we do not endorse this practice, since patients with Crohn disease who are at risk for relapse would be better served by taking medications of known efficacy.

The omega-3 free fatty acid formulation was well tolerated. In contrast to the results obtained in the study by Belluzzi et al,21 during the first month of treatment only 2.7% of patients had to discontinue the drug due to diarrhea. The increased tolerability was likely due to the gradual increase in dosing specified by the protocols. Although a theoretical risk of bleeding due to platelet dysfunction exists with omega-3 free fatty acid treatment,42,43 no serious bleeding problems were encountered despite the administration of a relatively high drug dose.

In summary, in the EPIC-1 and EPIC-2 trials administration of a high dose of omega-3 free fatty acids did not reduce the rate of relapse in patients with quiescent Crohn disease.

Corresponding Author: Brian G. Feagan, MD, Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, 100 Perth Dr, London, ON, Canada N6A 5K8 (bfeagan@robarts.ca).

Author Contributions: Dr Feagan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Feagan, Sandborn, Mittmann, Niv, Vandervoort, Rutgeerts.

Acquisition of data: Sandborn, Bar-Meir, D’Haens, Bradette, Cohen, Dallaire, Ponich, McDonald, Hébuterne, Klvana, Ardizzone, Alexeeva, Rostom, Kiudelis, Spleiss, Gilgen.

Analysis and interpretation of data: Feagan, Sandborn, Mittmann, Bar-Meir, Paré, Wong, Zou, Donner, Rutgeerts.

Drafting of the manuscript: Feagan, Hébuterne, Klvana, Ardizzone, Kiudelis.

Critical revision of the manuscript for important intellectual content: Feagan, Sandborn, Mittmann, Bar-Meir, D’Haens, Bradette, Cohen, Dallaire, Ponich, McDonald, Paré, Niv, Alexeeva, Rostom, Spleiss, Gilgen, Vandervoort, Wong, Zou, Donner, Rutgeerts.

Statistical analysis: Wong, Zou, Donner.

Obtained funding: Sandborn, Klvana, Alexeeva, Spleiss, Rutgeerts.

Administrative, technical, or material support: Feagan, Sandborn, Bar-Meir, D’Haens, Spleiss, Gilgen, Vandervoort.

Study supervision: Feagan, Mittmann, Cohen, Dallaire, Ponich, McDonald, Hébuterne, Paré, Klvana, Ardizzone, Alexeeva, Kiudelis, Vandervoort, Rutgeerts.

Financial Disclosures: Dr Feagan reported receiving grant and research support from Schering-Plough, Otsuka, Milllennium, Tillotts, Abbott, Protein Design Labs, Boehringer-Ingelheim, Novartis, Centocor, Berlex, Synta, Schering Canada, Elan/Biogen, UCB Pharma, BMS, Proctor & Gamble, and Napo Pharma; receiving consulting fees from Synta, Millennium, Schering Canada, Celltech, Centocor, Elan/Biogen, Janssen-Ortho, Protein Design Labs, ISIS, Teva Pharmaceuticals, Santarus, Schering-Plough, Bristol-Myers Squibb, Celgene, CombinatorRx Inc, UCB Pharma, Napo Pharma, Abbott, Proctor & Gamble, Osiris, Berlex, AstraZeneca, GeneLogic Inc, Cerimon Pharm, Tioga Pharm, Serono, Genentech, Tillotts Pharma AG, and CombinatoRx Inc; serving on the apeakers bureau of AstraZeneca; and serving on the scientific advisory board of Protein Design Labs, AstraZeneca, Elan/Biogen, Celltech, Synta, Schering Canada, Celgene, and Tillotts Pharma AG. Dr Sandborn reported receiving grants or funding from Abbott Laboratories, Bristol-Meyers Squibb, Centocor, Chemocentryx, Elan Pharmaceuticals Inc, Otsuka American Pharmaceuticals Inc, PDL Biopharma, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals Inc, Schering-Plough, Serono, Shire Pharmaceuticals, Targacept Inc, Techlab Inc, Tillotts Pharma AG, and UCB Pharma (previously Celltech Therapeutics Ltd); receiving consulting fees from GlaxoSmithKline (previously Glaxo Wellcome), Abbott Laboratories (fees paid to the Mayo Clinic), ActoGeniX NV, AGI Therapeutics Inc, Ajinomoto Pharmaceuticals, Alba Therapeutics, Alizyme plc, Alza, Amgen Inc, Ardea Biosciences, Aspreva Pharmaceuticals, AstraZeneca, Atrix Laboratories Inc (acquired by QLT in 2004), Avidia Inc, Berlex, Bexel Pharmaceuticals Inc, BioBalance, Boehringer-Ingelheim Inc, Bristol Meyers Squibb, Celegene, Celltech (acquired by UCB Pharma in 2004) (fees paid to the Mayo Clinic), Centocor (fees paid to the Mayo Clinic), Cerimon Pharmaceutical Inc, Chemocentryx, CombinatoRx Inc, CoMentis, Corautus Genetics, Cosmo Technologies Ltd, CuraGen, Effective Pharmaceuticals Inc, Eisai Medical Research Inc, Elan Pharmaceuticals Inc, Enteromedics, Enzo Therapeutics Inc, Eurand, FlexPharm Ltd (previously named Enterotech), Genencor International, Genentech, H3 Pharma (name changed to Debiopharm SA in 2005), Hoffman LaRoche Inc (Roche), Hutchison Medipharma Ltd, Inflabloc Pharmaceuticas (previously named Pharmadigm Inc), Inotek Pharmaceutical, ISIS Pharmaceuticals, Jacobus Pharmaceutical Co, Johnson & Johnson Pharmaceutical Research & Development, LigoCyte Pharmaceuticals, McNeil Consumer and Specialty Pharmaceuticals, Medarex Inc, Merck Research Laboratories, Millennium Pharmaceuticals Inc, Nisshin Kyorin Pharmaceutical Co Ltd, Novartis, NPS Pharmaceuticals, Ocera Therapeutics Inc (previously named Renovia Inc), Ono Pharma USA, Otsuka American Pharmaceuticals Inc, PDL Biopharma (previously named Protein Design Labs) (fees paid to the Mayo Clinic), Pfizer, Procter & Gamble (fees paid to the Mayo Clinic), Prometheus Laboratories, Renovis Inc, Salix Pharmaceuticals Inc, Sangstat (acquired by Genzyme in 2003), Schering-Plough, Serono Inc, Shire Pharmaceuticals, Synta Pharmaceuticals, Targacept, Teva Pharmaceuticals, Therakos, Tioga Pharmaceuticals, UCB Pharma (fees paid to the Mayo Clinic), Vela Pharmaceuticals Inc, and ViaCell Inc; and receiving honoraria for speaking at continuing medical education events indirectly sponsored by Abbott Laboratories, Axcan Pharmaceuticals, AstraZeneca, Centocor, Elan Pharmaceuticals Inc, Falk Pharma, Otsuka American Pharmaceuticals Inc, PDL Biopharma, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals Inc, Schering-Plough, Shire Pharmaceuticals, and UCB Pharma. Dr Mittmann reported receiving product development consultancy fees from Tillotts Pharma AG. Dr Bar-Meir reported receiving consulting fees from Tillotts Pharma AG. Dr Rostom reported receiving consulting fees from Novartis and Bayer and an unrestricted educational grant from ALBA Therapeutics. Mr Spleiss reported having employee equity ownership in Tillotts Pharma AG. Dr Rutgeerts reported receiving consulting fees from Centocor, Schering-Plough, UCB Abbott, Elan-Biogen, PDL, Avidia, Bristol-Myers Squibb, Millennium, and Tillotts; lecture fees from Centocor, Schering-Plough, UCB, Abbott, and Elan-Biogen; and grant support from Centocor, Schering-Plough, Abbott, and UCB. Drs D’Haens, Bradette, Cohen, Dallaire, Ponich, McDonald, Kiudelis, Hebuterne, Paré, Klvana, Niv, Ardizzone, Alexeeva, and Rostom were site investigators and were compensated for performing clinical measurements. No other financial disclosures were reported.

Funding/Support: This study was funded by Tillotts Pharma.

Role of the Sponsor: The trial was designed by the academic investigators in collaboration with representatives of Tillotts, and representatives of Tillotts reviewed and approved the final version of the manuscript.

Data and Safety Monitoring Board:University of Health Sciences Center, Denver, Colorado: J. Singleton; Charité-Universitätsmedizin Berlin: H. Lochs; Wolfson Institute of Preventative Medicine, London, UK: J. Cuzick. Data Coordinating Center:Robarts Clinical Trials, Robarts Research Institute, The University of Western Ontario, London, Ontario: F. Babar, B. Bergman, M. Bertin, T. Clayton, M. Hammond, M. Hopkins, L. Jensen, E. Karugu, L. Liddiard, F. Livingstone, M. Mathers, C. Mueller, S. Nelson, J. Rémillard, I. Ruocco, B. Sarazin, B. Sharpe, L. Smith, H. Sun, K. Toulouse. Participating Investigators:Atlanta Gastroenterology Associates, Atlanta, Georgia: D. Wolf, M. Monroe; Carle Clinic Association, Urbana, Illinois: E. Greenberg, V. Carlton; Cleveland Clinic Foundation, Cleveland, Ohio: D. Seidner, S. Zurc; Clinical Research Institute of Michigan, Chesterfield: R. Fogel, A. Leyson-Fiel; Health Sciences Centre, Calgary, Alberta: R. Panaccione, A. Daye; Health Sciences Centre, Edmonton, Alberta: R. Fedorak, C. McCabe-Woodrow; Health Sciences Centre, Winnipeg, Manitoba: C. Bernstein, T. Rawsthorne; Hôpital Maisonneuve-Rosemont, Montreal, Québec: G. Aumais, L. Henri; Hôpital St-Sacrement, Québec City, Québec: P. Paré, S. Rousseau; Hôtel Dieu de Levis, Levis, Québec: R. Bourdages, M. Berberi; Hotel Dieu Hospital, Kingston, Ontario: W. Depew, D. Brady; Jewish General Hospital, Montreal, Québec: A. Cohen, N. Desjardins; LAIR Centre, Vancouver, British Coumbia: F. Anderson, I. Wong; London Health Sciences Centre South Street Campus, London Ontario: T. Ponich, P. Walton-Mennill; London Health Sciences Centre University Campus, London, Ontario: J. McDonald, W. McCaw; Long Island Clinical Research Associates, Great Neck, New York: S. Katz, M. Mustac; Mayo Clinical Rochester, Minnesota: W. Sandborn, R. Jeche; Montreal General Hospital, Montreal, Québec: G. Wild, N. Pellerin; Mount Sinai Hospital, Toronto, Ontario: H. Steinhart, S. Mikolainis; Pavillon-Hôtel-Dieu de Québec CHUQ, Québec City, Québec: M. Bradette, S. Lepire; Pavillon St-François d’Assise CHUQ, Québec City, Québec: C. Dallaire, F. Bernard; Royal Alexandra Hospital, Edmonton, Albaerta: R. Bailey, D. Meyer; Royal Victoria Hospital, Montreal, Québec: A. Bitton, M. Bernier; Saint John Regional Hospital, Saint John, New Brunswick: A. Cockeram, H. Long; St Joseph's Health Centre, London, Ontario: R. Sy, L. Moyer; St Michael's Hospital, Toronto, Ontario: J. Baker, G. Stewart; St Paul's Hospital GI Research, Vancouver, British Columbia: R. Enns, S. Patterson; Sunnybrook & Women's College Health Science Centre, Toronto, Ontario: F. Saibil, M. Morgan; The Ottawa Hospital-Civic Campus, Ottawa, Ontario: A. Rostom, P. Waddell; University of Chicago Medical Center, Chicago, Illinois: S. Hanauer, H. Brenner; University of Kentucky Medical Branch, Lexington: T. Winter, J. Reynolds; University of North Carolina at Chapel Hill: K. Isaacs; D. Walkup; University of Texas Medical Branch, Galveston: J. Sellin, J. Hirsch; Victoria General Hospital QEII Health Sciences Centre, Halifax, Nova Scotia: D. MacIntosh, C. Kelly; Albrecht-Ludwigs-University, Freiburg, Germany: J. Rasenack, I. Borsukiewicz-Krupa; Internistische Praxis, Medizin, Berlin, Germany: H.-J. Kramm, I. Borsukiewicz-Krupa; Barzilai Medical Center, Ashkelon, Israel: M. Faschik, I. Rosen-Leibowitz; CHU de Grenoble, Grenoble, France: B. Bonaz, S. Zachayus; District Hospital, Usti nad Orlici, Czech Republic: L. Gabalec. L. Pribylova; District Hospital, Ceske Budejovice, Czech Republic: O. Shonova, L. Pribylova; Faculty Hospital, Prague, Czech Republic: J. Benes, L. Pribylova; Hadassah University Hospital, Jerusalem, Israel: E. Goldin, I. Rosen-Leibowitz; Heilig Hartziekenhuis, Roeselare, Belgium: F. Baert, W. Walravens; Hillel Yaffe Medical Center, Hadera, Israel: Z. Fireman, I. Rosen-Leibowitz; Hôpital Civil, Strasbourg, France: D. Vetter, S. Zachayus; Hôpital Saint Antoine, Paris, France: J. P. Gendre, S. Zachayus; Hospital Nord, Marseille, France: J.-C. Grimaud, S. Zachayus; Imelda Ziekenhuis, Bonheiden, Belgium: G. D’Haens, K. Lauwers; Internistische Gemeinschaftspraxis, Rödermark-Oberroden, Germany: S. Orlemann, I. Borsukiewicz-Krupa; Kaunas Medical University Clinics, Kaunas, Lithuania: G. Kiudelis, L. Didziapetriene; Klinikum der Universität Regensburg, Regensburg, Germany: H. Herfarth, I. Borsukiewicz-Krupa; Klinikum Mannheim, Mannheim, Germany: U. Böcker, I. Borsukiewicz-Krupa; Masaryk Hospital, Usti nad Labem, Czech Republic: J. Stehlik, L. Pribylova; Medizinische Hochschule Hannover, Hannover, Germany: M. Manns, I. Borsukiewicz-Krupa; Medizinische Universitäts, Erlangen, Germany: D. Raithel, I. Borsukiewicz-Krupa; Ospedale G. B Morgagni, Forli, Italy: D. Valpiani, P. Zamboni; Ospedale Luigi Sacco, Milan, Italy: S. Ardizzone, P. Zamboni; Ospedale Nuovo, Imola, Italy: C. Brignola, P. Zamboni; Ospedale Santissima Annunziata, Cento, Italy: G. Zoli, P. Zamboni; Policlinico S. Orsola Malpighi, Bologna, Italy: A. Belluzzi, T. Perrone; Rabin Medical Center Beilinson Campus, Petah Tiqwa, Israel: Y. Niv, O. BenShitrit; Ranbam Medical Center, Haifa, Israel: A. Eliakim, I. Rosen-Leibowitz; Soroka University Medical Center, Beer Sheva, Israel: A. Fich, I. Rosen-Leibowitz; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel: I. Dotan, I. Rosen-Leibowitz; The Chaim Sheba Medical Center, Tel Hashomer, Israel: A. Lang, I. Rosen-Leibowitz; The Edith Wolfson Medical Center, Holon, Israel: Y. Avni, I. Rosen-Leibowitz; ULB Hôpital Erasme, Brussels, Belgium: A. Van Gossum, W. Walravens; University Hospital, Ostrava, Czech Republic: P. Klvana, L. Pribylova; University Hospital, Pilzen, Czech Republic: J. Kozeluhova, L. Pribylova; University of Nice Sophia Antipolis, Nice, France: X. Hébuterne; UZ Gashuisberg, Leuven, Belgium: P. Rutgeerts, K. Lauwers; Vilnius University Hospital, Vilnius, Lithuania: A. Irnius, L Didziapetriene; Western Galilee Hospital, Nahariya, Israel: R. Reshef, I. Rosen-Leibowitz; Clinical Hospital, #33, Nizhyn Novgorod, Russia : O. Alexeeva, S. Krishtopenko, E. Galperin, O. Chertkova; Military Medical Academy, St. Petersburg, Russia : V. Grinevich, I. Gubonina, A. Pershko; St. Petersburg Medical Academy, St. Petersburg, Russia : A. Baranovsky, O. Shchukina, E. Kondrashina; Medical Academy, St. Petersburg, Russia : V. Simanenkov, E. Poroshina, O. Solovyeva; Moscow Regional Research Clinical Institute, Moscow, Russia : E. Belousova, O. Kuzmina, I. Domareva; Regional Clinical Hospital, Yaroslaval, Russia : O. Khrustalev, O. Okhapkina, S. Tsybulko.

Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease.  Cochrane Database Syst Rev. 2005;(1):CD003715
PubMed
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn's disease.  Gut. 1995;37(5):674-678
PubMed   |  Link to Article
Feagan BG, Fedorak RN, Irvine EJ,  et al; North American Crohn's Study Group Investigators.  A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease.  N Engl J Med. 2000;342(22):1627-1632
PubMed   |  Link to Article
Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double-blind study.  N Engl J Med. 1980;302(18):981-987
PubMed   |  Link to Article
Hanauer SB, Feagan BG, Lichtenstein GR,  et al.  Maintenance infliximab for Crohn's disease: the ACCENT 1 randomised trial.  Lancet. 2002;359(9317):1541-1549
PubMed   |  Link to Article
Colombel JF, Sandborn WJ, Rutgeerts P,  et al.  Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.  Gastroenterology. 2007;132(1):52-65
PubMed   |  Link to Article
Schreiber S, Khaliq-Kareemi M, Lawrance I,  et al.  Maintenance therapy with certolizumab pegol for Crohn's disease.  N Engl J Med. 2007;357(3):239-250
PubMed   |  Link to Article
Sandborn WJ, Feagan BG, Stoinov S,  et al.  Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med. 2007;357(3):228-238
PubMed   |  Link to Article
Nurmohamed MT, Dijkmans BA. Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis.  Drugs. 2005;65(5):661-694
PubMed   |  Link to Article
Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease.  Gastroenterology. 1998;115(4):813-821
PubMed   |  Link to Article
Keane J, Gershon S, Wise RP,  et al.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.  N Engl J Med. 2001;345(15):1098-1104
PubMed   |  Link to Article
Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.  Pain. 2007;129(1-2):210-223
PubMed   |  Link to Article
Stamp LK, James MJ, Cleland LG. Diet and rheumatoid arthritis: a review of the literature.  Semin Arthritis Rheum. 2005;35(2):77-94
PubMed   |  Link to Article
Donadio JV Jr, Larson TS, Bergstralh EJ, Grande JP. A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy.  J Am Soc Nephrol. 2001;12(4):791-799
PubMed
Durrington PN, Bhatnagar D, Mackness MI,  et al.  An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.  Heart. 2001;85(5):544-548
PubMed   |  Link to Article
Bays H. Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids.  Am J Cardiol. 2006;98(4A):71i-76i
PubMed   |  Link to Article
Stalenhoef AF, de Graaf J, Wittekoek ME, Bredie SJ, Demacker PN, Kastelein JJ. The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.  Atherosclerosis. 2000;153(1):129-138
PubMed   |  Link to Article
Yokoyama M, Origasa H, Matsuzaki M,  et al.  Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.  Lancet. 2007;369(9567):1090-1098
PubMed   |  Link to Article
Marchioli R, Barzi F, Bomba E,  et al.  Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardio (GISSI)-Prevenzione.  Circulation. 2002;105(16):1897-1903
PubMed   |  Link to Article
Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.  Am J Med. 2002;112(4):298-304
PubMed   |  Link to Article
Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease.  N Engl J Med. 1996;334(24):1557-1560
PubMed   |  Link to Article
Lorenz-Meyer H, Bauer P, Nicolay C,  et al; Study Group Members (German Crohn's Disease Study Group).  Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease: a randomized controlled multicenter trial.  Scand J Gastroenterol. 1996;31(8):778-785
PubMed   |  Link to Article
Best WR, Becktel JM, Singleton J, Kern F Jr. Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study.  Gastroenterology. 1976;70(3):439-444
PubMed
Summers RW, Switz DM, Sessions JT Jr,  et al.  National Cooperative Crohn's Disease Study: results of drug treatment.  Gastroenterology. 1979;77(4, pt 2):847-869
PubMed
Greenberg GR, Feagan BG, Martin F,  et al.  Oral budesonide for active Crohn's disease.  N Engl J Med. 1994;331(13):836-841
PubMed   |  Link to Article
Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection.  Med Care. 1992;30(6):473-483
PubMed   |  Link to Article
International Federation of Pharmaceutical Manufacturers Associations.  Medical Dictionary for Regulatory Activities (MedDRA) Version 9.0Chantilly, VA: MedDRA MSSO; 2007
 SAS Statistical Software Version 8.2. Cary, NC: SAS Institute Inc; 2001
 StatXact Version Version 8.0 With Cytel Studio Version 8. Cambridge, MA: Cytel Inc; 2007
Sandborn WJ, Colombel JF, Enns R,  et al.  Natalizumab induction and maintenance therapy for Crohn's disease.  N Engl J Med. 2005;353(18):1912-1925
PubMed   |  Link to Article
Greenberg GR, Feagan BG, Martin F,  et al; Canadian Inflammatory Bowel Disease Study Group.  Oral budesonide as maintenance treatment for Crohn's disease: a placebo-controlled, dose-ranging study.  Gastroenterology. 1996;110(1):45-51
PubMed   |  Link to Article
 Harmonised Tripartite Guideline ICH: Guideline for Good Clinical Practice E6(R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Web site. 1996. http://www.ich.org/LOB/media/MEDIA482.pdf. Accessibility verified March 12, 2008
Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity.  Lancet. 1980;1(8167):514
PubMed   |  Link to Article
Kjaergard LL, Villumsen J, Cluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.  Ann Intern Med. 2001;135(11):982-989
PubMed   |  Link to Article
Gluud LL. Bias in clinical intervention research.  Am J Epidemiol. 2006;163(6):493-501
PubMed   |  Link to Article
Kjaergard LL, Nikolova D, Gluud C. Randomized clinical trials in hepatology: predictors of quality.  Hepatology. 1999;30(5):1134-1138
PubMed   |  Link to Article
Hilsden RJ, Scott CM, Verhoef MJ. Complementary medicine use by patients with inflammatory bowel disease.  Am J Gastroenterol. 1998;93(5):697-701
PubMed   |  Link to Article
Heuschkel R, Afzal N, Wuerth A,  et al.  Complementary medicine use in children and young adults with inflammatory bowel disease.  Am J Gastroenterol. 2002;97(2):382-388
PubMed   |  Link to Article
Leong RW, Lawrance IC, Ching JY,  et al.  Knowledge, quality of life, and use of complementary and alternative medicine and therapies in inflammatory bowel disease: a comparison of Chinese and Caucasian patients.  Dig Dis Sci. 2004;49(10):1672-1676
PubMed   |  Link to Article
Li FX, Verhoef MJ, Best A, Otley A, Hilsden RJ. Why patients with inflammatory bowel disease use or do not use complementary and alternative medicine: a Canadian national survery.  Can J Gastroenterol. 2005;19(9):567-573
PubMed
Langmead L, Rampton DS. Review article: complementary and alternative therapies for inflammatory bowel disease.  Aliment Pharmacol Ther. 2006;23(3):341-349
PubMed   |  Link to Article
McClaskey EM, Michalets EL. Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature.  Pharmacotherapy. 2007;27(1):152-160
PubMed   |  Link to Article
Knapp HR, Reilly IA, Alexxandrini P, FitzGerald  GA. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis.  N Engl J Med. 1986;314(15):937-942
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Disposition of Patients During the Conduct of EPIC-1 and EPIC-2
Graphic Jump Location

EPIC indicates Epanova Program in Crohn’s Study.

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Estimates of the Time to Relapse in the Omega-3 Free Fatty Acids and Placebo Groups for EPIC-1 and EPIC-2
Graphic Jump Location

EPIC indicates Epanova Program in Crohn’s Study.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Patients in EPIC-1 and EPIC-2a
Table Graphic Jump LocationTable 2. Incidence of Adverse Events, EPIC-1 and EPIC-2a

References

Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease.  Cochrane Database Syst Rev. 2005;(1):CD003715
PubMed
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn's disease.  Gut. 1995;37(5):674-678
PubMed   |  Link to Article
Feagan BG, Fedorak RN, Irvine EJ,  et al; North American Crohn's Study Group Investigators.  A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease.  N Engl J Med. 2000;342(22):1627-1632
PubMed   |  Link to Article
Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double-blind study.  N Engl J Med. 1980;302(18):981-987
PubMed   |  Link to Article
Hanauer SB, Feagan BG, Lichtenstein GR,  et al.  Maintenance infliximab for Crohn's disease: the ACCENT 1 randomised trial.  Lancet. 2002;359(9317):1541-1549
PubMed   |  Link to Article
Colombel JF, Sandborn WJ, Rutgeerts P,  et al.  Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.  Gastroenterology. 2007;132(1):52-65
PubMed   |  Link to Article
Schreiber S, Khaliq-Kareemi M, Lawrance I,  et al.  Maintenance therapy with certolizumab pegol for Crohn's disease.  N Engl J Med. 2007;357(3):239-250
PubMed   |  Link to Article
Sandborn WJ, Feagan BG, Stoinov S,  et al.  Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med. 2007;357(3):228-238
PubMed   |  Link to Article
Nurmohamed MT, Dijkmans BA. Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis.  Drugs. 2005;65(5):661-694
PubMed   |  Link to Article
Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease.  Gastroenterology. 1998;115(4):813-821
PubMed   |  Link to Article
Keane J, Gershon S, Wise RP,  et al.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.  N Engl J Med. 2001;345(15):1098-1104
PubMed   |  Link to Article
Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.  Pain. 2007;129(1-2):210-223
PubMed   |  Link to Article
Stamp LK, James MJ, Cleland LG. Diet and rheumatoid arthritis: a review of the literature.  Semin Arthritis Rheum. 2005;35(2):77-94
PubMed   |  Link to Article
Donadio JV Jr, Larson TS, Bergstralh EJ, Grande JP. A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy.  J Am Soc Nephrol. 2001;12(4):791-799
PubMed
Durrington PN, Bhatnagar D, Mackness MI,  et al.  An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.  Heart. 2001;85(5):544-548
PubMed   |  Link to Article
Bays H. Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids.  Am J Cardiol. 2006;98(4A):71i-76i
PubMed   |  Link to Article
Stalenhoef AF, de Graaf J, Wittekoek ME, Bredie SJ, Demacker PN, Kastelein JJ. The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.  Atherosclerosis. 2000;153(1):129-138
PubMed   |  Link to Article
Yokoyama M, Origasa H, Matsuzaki M,  et al.  Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.  Lancet. 2007;369(9567):1090-1098
PubMed   |  Link to Article
Marchioli R, Barzi F, Bomba E,  et al.  Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardio (GISSI)-Prevenzione.  Circulation. 2002;105(16):1897-1903
PubMed   |  Link to Article
Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.  Am J Med. 2002;112(4):298-304
PubMed   |  Link to Article
Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease.  N Engl J Med. 1996;334(24):1557-1560
PubMed   |  Link to Article
Lorenz-Meyer H, Bauer P, Nicolay C,  et al; Study Group Members (German Crohn's Disease Study Group).  Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease: a randomized controlled multicenter trial.  Scand J Gastroenterol. 1996;31(8):778-785
PubMed   |  Link to Article
Best WR, Becktel JM, Singleton J, Kern F Jr. Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study.  Gastroenterology. 1976;70(3):439-444
PubMed
Summers RW, Switz DM, Sessions JT Jr,  et al.  National Cooperative Crohn's Disease Study: results of drug treatment.  Gastroenterology. 1979;77(4, pt 2):847-869
PubMed
Greenberg GR, Feagan BG, Martin F,  et al.  Oral budesonide for active Crohn's disease.  N Engl J Med. 1994;331(13):836-841
PubMed   |  Link to Article
Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection.  Med Care. 1992;30(6):473-483
PubMed   |  Link to Article
International Federation of Pharmaceutical Manufacturers Associations.  Medical Dictionary for Regulatory Activities (MedDRA) Version 9.0Chantilly, VA: MedDRA MSSO; 2007
 SAS Statistical Software Version 8.2. Cary, NC: SAS Institute Inc; 2001
 StatXact Version Version 8.0 With Cytel Studio Version 8. Cambridge, MA: Cytel Inc; 2007
Sandborn WJ, Colombel JF, Enns R,  et al.  Natalizumab induction and maintenance therapy for Crohn's disease.  N Engl J Med. 2005;353(18):1912-1925
PubMed   |  Link to Article
Greenberg GR, Feagan BG, Martin F,  et al; Canadian Inflammatory Bowel Disease Study Group.  Oral budesonide as maintenance treatment for Crohn's disease: a placebo-controlled, dose-ranging study.  Gastroenterology. 1996;110(1):45-51
PubMed   |  Link to Article
 Harmonised Tripartite Guideline ICH: Guideline for Good Clinical Practice E6(R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Web site. 1996. http://www.ich.org/LOB/media/MEDIA482.pdf. Accessibility verified March 12, 2008
Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity.  Lancet. 1980;1(8167):514
PubMed   |  Link to Article
Kjaergard LL, Villumsen J, Cluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.  Ann Intern Med. 2001;135(11):982-989
PubMed   |  Link to Article
Gluud LL. Bias in clinical intervention research.  Am J Epidemiol. 2006;163(6):493-501
PubMed   |  Link to Article
Kjaergard LL, Nikolova D, Gluud C. Randomized clinical trials in hepatology: predictors of quality.  Hepatology. 1999;30(5):1134-1138
PubMed   |  Link to Article
Hilsden RJ, Scott CM, Verhoef MJ. Complementary medicine use by patients with inflammatory bowel disease.  Am J Gastroenterol. 1998;93(5):697-701
PubMed   |  Link to Article
Heuschkel R, Afzal N, Wuerth A,  et al.  Complementary medicine use in children and young adults with inflammatory bowel disease.  Am J Gastroenterol. 2002;97(2):382-388
PubMed   |  Link to Article
Leong RW, Lawrance IC, Ching JY,  et al.  Knowledge, quality of life, and use of complementary and alternative medicine and therapies in inflammatory bowel disease: a comparison of Chinese and Caucasian patients.  Dig Dis Sci. 2004;49(10):1672-1676
PubMed   |  Link to Article
Li FX, Verhoef MJ, Best A, Otley A, Hilsden RJ. Why patients with inflammatory bowel disease use or do not use complementary and alternative medicine: a Canadian national survery.  Can J Gastroenterol. 2005;19(9):567-573
PubMed
Langmead L, Rampton DS. Review article: complementary and alternative therapies for inflammatory bowel disease.  Aliment Pharmacol Ther. 2006;23(3):341-349
PubMed   |  Link to Article
McClaskey EM, Michalets EL. Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature.  Pharmacotherapy. 2007;27(1):152-160
PubMed   |  Link to Article
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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