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Meta-Analysis
. 2020 Aug 28;8(8):CD000544.
doi: 10.1002/14651858.CD000544.pub5.

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis

Alistair Murray  1 , Tran M Nguyen  2 , Claire E Parker  2 , Brian G Feagan  2   3   4 , John K MacDonald  3
Affiliations
Meta-Analysis

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis

Alistair Murray et al. Cochrane Database Syst Rev. .

Abstract

Background: Oral 5-aminosalicylic acid (5-ASA; also known as mesalazine or mesalamine) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. In an earlier version of this review, we found that 5-ASA drugs were more effective than placebo for maintenance of remission of ulcerative colitis (UC), but had a significant therapeutic inferiority relative to SASP. In this version, we have rerun the search to bring the review up to date.

Objectives: To assess the efficacy, dose-responsiveness, and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent UC and to compare the efficacy and safety of once-daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens.

Search methods: We performed a literature search for studies on 11 June 2019 using MEDLINE, Embase, and the Cochrane Library. In addition, we searched review articles and conference proceedings.

Selection criteria: We included randomized controlled trials with a minimum treatment duration of six months. We considered studies of oral 5-ASA therapy for treatment of participants with quiescent UC compared with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose-ranging studies.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes were adherence, adverse events (AE), serious adverse events (SAE), withdrawals due to AEs, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus SASP, once-daily dosing versus conventional dosing, 5-ASA (balsalazide, Pentasa, and olsalazine) versus comparator 5-ASA formulation (Asacol and Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence.

Main results: The search identified 44 studies (9967 participants). Most studies were at low risk of bias. Ten studies were at high risk of bias. Seven of these studies were single-blind and three were open-label. 5-ASA is more effective than placebo for maintenance of clinical or endoscopic remission. About 37% (335/907) of 5-ASA participants relapsed at six to 12 months compared to 55% (355/648) of placebo participants (RR 0.68, 95% CI 0.61 to 0.76; 8 studies, 1555 participants; high-certainty evidence). Adherence to study medication was not reported for this comparison. SAEs were reported in 1% (6/550) of participants in the 5-ASA group compared to 2% (5/276) of participants in the placebo group at six to 12 months (RR 0.60, 95% CI 0.19 to 1.84; 3 studies, 826 participants; low-certainty evidence). There is probably little or no difference in AEs at six to 12 months' follow-up (RR 0.93, 95% CI 0.73 to 1.18; 5 studies, 1132 participants; moderate-certainty evidence). SASP is more effective than 5-ASA for maintenance of remission. About 48% (416/871) of 5-ASA participants relapsed at six to 18 months compared to 43% (336/784) of SASP participants (RR 1.14, 95% CI 1.03 to 1.27; 12 studies, 1655 participants; high-certainty evidence). Adherence to study medication and SAEs were not reported for this comparison. There is probably little or no difference in AEs at six to 12 months' follow-up (RR 1.07, 95% CI 0.82 to 1.40; 7 studies, 1138 participants; moderate-certainty evidence). There is little or no difference in clinical or endoscopic remission rates between once-daily and conventionally dosed 5-ASA. About 37% (717/1939) of once-daily participants relapsed over 12 months compared to 39% (770/1971) of conventional-dosing participants (RR 0.94, 95% CI 0.88 to 1.01; 10 studies, 3910 participants; high-certainty evidence). There is probably little or no difference in medication adherence rates. About 10% (106/1152) of participants in the once-daily group failed to adhere to their medication regimen compared to 8% (84/1154) of participants in the conventional-dosing group (RR 1.18, 95% CI 0.72 to 1.93; 9 studies, 2306 participants; moderate-certainty evidence). About 3% (41/1587) of participants in the once-daily group experienced a SAE compared to 2% (35/1609) of participants in the conventional-dose group at six to 12 months (RR 1.20, 95% CI 0.77 to 1.87; moderate-certainty evidence). There is little or no difference in the incidence of AEs at six to 13 months' follow-up (RR 0.98, 95% CI 0.92 to 1.04; 8 studies, 3497 participants; high-certainty evidence). There may be little or no difference in the efficacy of different 5-ASA formulations. About 44% (158/358) of participants in the 5-ASA group relapsed at six to 18 months compared to 41% (142/349) of participants in the 5-ASA comparator group (RR 1.08, 95% CI 0.91 to 1.28; 6 studies, 707 participants; low-certainty evidence).

Authors' conclusions: There is high-certainty evidence that 5-ASA is superior to placebo for maintenance therapy in UC. There is high-certainty evidence that 5-ASA is inferior compared to SASP. There is probably little or no difference between 5-ASA and placebo, and 5-ASA and SASP in commonly reported AEs such as flatulence, abdominal pain, nausea, diarrhea, headache, and dyspepsia. Oral 5-ASA administered once daily has a similar benefit and harm profile as conventional dosing for maintenance of remission in quiescent UC.

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Conflict of interest statement

AM: none.

TMN: none.

CEP: none.

JKM: none.

BGF has received fees from Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol‐Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma for Scientific Advisory Board membership; fees from Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner‐Chilcott, Wyeth, Zealand, and Zyngenia for consultancy; payment for lectures from Abbott/AbbVie, JnJ/Janssen, Takeda, Warner‐Chilcott, UCB Pharma; his institution has received grants/grants pending from Abbott/AbbVie, Amgen, Astra Zeneca, Bristol‐Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, and UCB Pharma.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 1: Failure to maintain clinical or endoscopic remission at 6–12 months
1.2
1.2. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 2: Development of any adverse event at 6–12 months
1.3
1.3. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 3: Development of any adverse event (sensitivity analysis) at 6–12 months
1.4
1.4. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 4: Development of any serious adverse event at 6–12 months
1.5
1.5. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 5: Withdrawal from study due to adverse event at 6–12 months
1.6
1.6. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 6: Withdrawal from study due to adverse event (sensitivity analysis) at 6–12 months
1.7
1.7. Analysis
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 7: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
2.1
2.1. Analysis
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
2.2
2.2. Analysis
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 2: Failure to maintain remission (trials without olsalazine) at 6–12 months
2.3
2.3. Analysis
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 3: Development of any adverse event at 6–18 months
2.4
2.4. Analysis
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 4: Withdrawal from study due to adverse event at 6–18 months
2.5
2.5. Analysis
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–18 months
3.1
3.1. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 1: Failure to maintain clinical or endoscopic remission at 6 months
3.2
3.2. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 2: Failure to maintain clinical or endoscopic remission at 12–13 months
3.3
3.3. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 3: Failure to adhere to study medication regimen at study endpoint at 6–13 months
3.4
3.4. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 4: Failure to adhere to study medication regimen at 6–13 months (sensitivity analysis – excluding outliers)
3.5
3.5. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 5: Development of any adverse event at 6–13 months
3.6
3.6. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 6: Development of serious adverse events at 6–13 months
3.7
3.7. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 7: Withdrawal due to adverse event at 6–13 months
3.8
3.8. Analysis
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 8: Exclusion/withdrawal after entry (not due to relapse) at 6–13 months
4.1
4.1. Analysis
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
4.2
4.2. Analysis
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 2: Development of any adverse event at 6–12 months
4.3
4.3. Analysis
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 3: Development of any serious adverse event at 12 months
4.4
4.4. Analysis
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 4: Withdrawal from study due to adverse event at 6–12 months
4.5
4.5. Analysis
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
5.1
5.1. Analysis
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
5.2
5.2. Analysis
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 2: Development of any adverse event at 6–12 months
5.3
5.3. Analysis
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 3: Development of any serious adverse event at 6–12 months
5.4
5.4. Analysis
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 4: Withdrawal from study due to adverse event at 6–12 months
5.5
5.5. Analysis
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
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McIntyre 1988 {published data only}
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    1. McIntyre PB, Rodrigues CA, Lennard-Jones JE, Barrison IG, Walker JG, Baton JH, et al. Balsalazine in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Alimentary Pharmacology and Therapeutics 1988;2:237-43. - PubMed
Miner 1995 {published data only}
    1. Miner P, Hanauer S, Robinson M, Schwartz J, Arora S, Pentasa UC Maintenance Study Group. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Digestive Diseases and Sciences 1995;40:296-304. - PubMed
    1. Miner P, Schwartz J, Aora S, Robinson M, Hanauer S, the Pentasa Study Group. Maintenance of remission in ulcerative colitis (UC) patients with controlled-release mesalamine capsules (Pentasa). Gastroenterology 1992;102:A666.
Mulder 1988 {published data only}
    1. Mulder CJ, Tytgat GN, Weterman IT, Dekker W, Blok P, Schrijver M, et al. Double-blind comparison of slow-release 5-aminosalicylate and sulfasalazine in remission maintenance in ulcerative colitis. Gastroenterology 1988;95:1449-53. - PubMed
    1. Mulder CJ, Tytgat GN, Weterman IT. Double blind evaluation of slow-release 5-aminosalicylic acid (Pentasa) and salazopyridin (Salazopyrin) in the maintenance therapy of ulcerative colitis. Gastroenterology 1988;94(5 Part 2):A313.
Nilsson 1995 {published data only}
    1. Nilsson A, Danielsson A, Lofberg R, Benno P, Bergman L, Fausa O, et al. Olsalazine versus sulphasalazine for relapse prevention in ulcerative colitis: a multicenter study. American Journal of Gastroenterology 1995;90:381-7. - PubMed
Paoluzi 2005 {published data only}
    1. Paoluzi OA, Iacopini F, Pica R, Crispino P, Marcheggiano A, Consolazio A, et al. Comparison of two different daily dosages (2.4 vs. 1.2 g) of oral mesalazine in maintenance of remission in ulcerative colitis patients: 1-year follow-up study. Alimentary Pharmacology and Therapeutics 2005;21(9):1111-9. - PubMed
    1. Paoluzi OA, Pica R, Crispino P, Iacopini F, Consolazio A, Rivera M, et al. Doubling daily dosage of oral mesalazine (2.4 vs. 1.2 g) in the maintenance therapy of pts with ulcerative colitis delays but does not reduce incidence of relapses: a 1-year follow-up study. Gastroenterology 2005;128(4 Suppl 2):A585.
Park 2019 {published data only}
    1. Park SK, Eun CS, Seo GS, Lim J, Kim TO, Park DI. The effects and adherence of Asacol comparing 2.4 g once daily with 800 mg three times or 1200 mg twice daily for maintain therapy in the ulcerative colitis: prospective multicentre randomised study. Journal of Crohn's & Colitis 2018;12(Suppl 1):S367.
    1. Park SK, Park SH, Eun CS, Seo GS, Im JP, Kim TO, et al. Adherence to Asacol once daily versus divided regimen for maintenance therapy in ulcerative colitis: a prospective, multicenter, randomized study. Intestinal Research 2019;17(3):349-56. - PMC - PubMed
Pica 2012 {published data only}
    1. Pica R, Cassieri C, Cocco A, Marcheggiano A, Occhigrossi G, Zippi M, et al. Randomised open label trial comparing two different dosages of oral mesalazine in the maintenance treatment of ulcerative colitis. Italian Journal of Medicine 2012;1:108.
Prantera 2009 {published data only}
    1. Kohn A, Prantera C, Caprilli R, Campieri M, Cottone M, Pallone F, et al. Maintenance treatment of ulcerative colitis with 5-aminosalicylic acid (5-ASA): results from the Italian population of a one year, randomized, multinational study comparing MMx® with Asacol®. Gastroenterology 2009;136(5 Suppl 1):390.
    1. Prantera C, Kohn A, Campieri M, Caprilli R, Cottone M, Pallone F, et al. Clinical trial: ulcerative colitis maintenance treatment with 5-ASA: a 1-year, randomized multicentre study comparing MMX with Asacol. Alimentary Pharmacology and Therapeutics 2009;30(9):908-18. - PubMed
Rijk 1992 {published data only}
    1. Rijk MC, Lier HJ, Tongerson JH. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: prospective, double-blind, randomized multicenter study. American Journal of Gastroenterology 1992;87:438-42. - PubMed
    1. Rijk MC, Tongersen JH. The relapse preventing effect and safety of sulphasalazine and olsalazine in patients with ulcerative colitis in remission. Gastroenterology 1991;100(5 Part 2):A243.
Riley 1988 {published data only}
    1. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment of patients with ulcerative colitis. Gastroenterology 2012;29(5):669-74. - PubMed
    1. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988;94:1383-9. - PubMed
    1. Riley SA, Mani V, Goodman MJ, Turnberg LA. A comparison of delayed-release 5-ASA and sulfasalazine as maintenance treatment in ulcerative colitis. Gastroenterology 1987;92:A1596. - PubMed
    1. Riley SA, Mani V, Goodman MJ, Turnberg LA. A comparison of delayed-release 5-aminosalicylic acid (5-ASA) and sulfasalazine (SSZ) as maintenance treatment of ulcerative colitis (UC). Gut 1987;28:1390.
Rutgeerts 1989 {published data only}
    1. Rutgeerts P. Comparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 1989;3:183-91. - PubMed
Sandberg‐Gertzen 1986 {published data only}
    1. Jarnerot G, Sandberg-Gertzen H. Azodisal sodium, (ADS), Dipentum, as relapse prevention in ulcerative colitis (UC). A double-blind placebo controlled study. Gastroenterology 1985;88(5 Part 2):A1432.
    1. Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis: a study of tolerance and relapse prevention properties. Gastroenterology 1986;90:1024-30. - PubMed
Sandborn 2010 {published data only}
    1. Sandborn W, Kane S, Korzenik J, Lashner B, Leighton J, Mahadevan U, et al. Once daily dosing of delayed-release oral mesalamine for maintenance of remission of ulcerative colitis (the QDIEM trial): 6 and 12 month results. Inflammatory Bowel Diseases 2009;15:S15.
    1. Sandborn WJ, Korzenik J, Lashner B, Leighton JA, Mahadevan U, Marion JF, et al. Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis. Gastroenterology 2010;138(4):1286-96. - PubMed
Suzuki 2017 {published data only}
    1. Suzuki Y, lida M, Ito H, Nishino H, Ohmori T, Arai T, et al. 2.4g Mesalamine (Asacol 400mg tablet) once daily is as effective as three times daily in maintenance of remission in ulcerative colitis: a randomized, noninferiority, multi-center trial. Inflammatory Bowel Diseases 2017;23(5):822-32. - PMC - PubMed
Travis 1994 {published data only}
    1. Travis SP, Tysk C, Silva HJ, Sandberg-Gertzen H, Jewell DP, Jarnerot G. Optimum dose of olsalazine for maintaining remission in ulcerative colitis. Gut 1994;35:1282-6. - PMC - PubMed
Watanabe 2013 {published data only}
    1. Watanabe M, Hanai H, Nishino H, Yokoyama T, Terada T, Suzuki Y. Comparison of QD and TID oral mesalazine for maintenance of remission in quiescent ulcerative colitis: a double-blind, double-dummy, randomized multicenter study. Inflammatory Bowel Diseases 2013;19(8):1681-90. - PubMed
Wright 1993 {published data only}
    1. Wright JP, O'Keefe EA, Cuming L, Jaskiewicz K. Olsalazine in maintenance of clinical remission in patients with ulcerative colitis. Digestive Diseases and Sciences 1993;38:1837-42. - PubMed
    1. Wright JP, O'Keefe EA, Cuming L, Jaskiewicz K. Olsalazine in the maintenance of remission in patients with ulcerative colitis. Gastroenterology 1992;102:A714. - PubMed

References to studies excluded from this review

Andreoli 1994 {published data only}
    1. Andreoli A, Spinella S, Levenstein S, Prantera C. 5-ASA enema versus oral sulphasalazine in maintaining remission in ulcerative colitis. Italian Journal of Gastroenterology 1994;26(3):121-5. - PubMed
Bardazzi 1994 {published data only}
    1. Bardazzi G, d'Albasio G, Bonanomi AG, Trallori G, Messori A, Amorosi A, et al. Intermittent versus continuous 5-aminosalicylic acid treatment for maintaining remission in ulcerative colitis. Italian Journal of Gastroenterology 1994;26(7):334-7. - PubMed
d'Albasio 1997 {published data only}
    1. d'Albasio G, Pacini F, Camarri E, Messori A, Trallori G, Bonanomi AG, et al. Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomized double-blind study. American Journal of Gastroenterology 1997;92(7):1143-7. - PubMed
D'Haens 2017 {published data only}
    1. D'Haens GR, Sandborn WJ, Zou G, Stitt LW, Rutgeerts PJ, Gilgen D, et al. Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis. Alimentary Pharmacology & Therapeutics 2017;46(3):292-302. - PubMed
Dew 1982b {published data only}
    1. Dew MJ, Hughes P, Harries AD, Williams G, Evans BK, Rhodes J. Maintenance of remissions in ulcerative colitis with oral preparation of 5-aminosalicylic acid. British Medical Journal 1982;285:1012. - PMC - PubMed
Dignass 2009b {published data only}
    1. Dignass A, Bokemeyer B, Stijnen T, Tan T, Borner N, Oudkerk Pool M, et al. Safety of once-daily vs twice-daily mesalazine (Pentasa) dosing. Results from a 12-month randomised controlled trial in maintenance of remission of ulcerative colitis. In: Canadian Journal of Gastroenterology. Vol. 23. 2009.
Dignass 2018 {published data only}
    1. Dignass A, Schnabel R, Romatowski J, Pavlenko V, Dorofeyev A, Derova J. Efficacy and safety of a novel high-dose mesalazine tablet in mild to moderate active ulcerative colitis: a double-blind, multicentre, randomised trial. United European Gastroenterology Journal 2018;6(1):138-47. - PMC - PubMed
Eliakim 1990 {published data only}
    1. Eliakim R, Wengrower D, Ligumsky M, Rachmilewitz D. Comparable efficacy of oral 5-ASA (Mesasal) and sulfasalazine in maintaining ulcerative colitis in remission. Israel Journal of Medical Sciences 1990;26(1):47-9. - PubMed
Ewe 1996 {published data only}
    1. Ewe K, Becker K, Ueberschaer B. Systemic uptake of 5-aminosalicylic acid from olsalazine and Eudragit L coated mesalazine in patients with ulcerative colitis in remission. Zeitschrift fur Gastroenterologie 1996;34(4):225-9. - PubMed
Fernández‐Bañares 1999 {published data only}
    1. Fernández-Bañares F, Hinojosa J, Sánchez-Lombraña JL, Navarro E, Martínez-Salmerón JF, García-Pugés A, et al. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. American Journal of Gastroenterology 1999;94(2):427-33. - PubMed
Frieri 2005 {published data only}
    1. Frieri G, Pimpo M, Galletti B, Palumbo G, Corrao G, Latella G, et al. Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis. Digestive and Liver Disease 2005;37(2):92-6. - PubMed
Giaffer 1992b {published data only}
    1. Giaffer MH, O'Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant or allergic to sulphasalazine. Alimentary Pharmacology and Therapeutics 1992;6(1):51-9. - PubMed
Gillespie 2014 {published data only}
    1. Gillespie D, Hood K, Farewell D, Stenson R, Probert C, Hawthorne AB. Electronic monitoring of medication adherence in a 1-year clinical study of 2 dosing regimens of mesalazine for adults in remission with ulcerative colitis. Inflammatory Bowel Diseases 2014;20(1):82-91. - PubMed
Gionchetti 1990 {published data only}
    1. Gionchetti P, Campieri M, Belluzzi A, Brignola C, Tampieri M, Iannone P, et al. Pentasa in maintenance treatment of ulcerative colitis. Gastroenterology 1990;98:251. - PubMed
Gionchetti 1996 {published data only}
    1. Gionchetti P, Campieri M, Venturi A, Rizzello F, Ferretti M, Brignola C, et al. Systemic availability of 5-aminosalicylic acid: comparison of delayed release and an azo-bond preparation. Alimentary Pharmacology and Therapeutics 1996;10(4):601-5. - PubMed
Green 2004 {published data only}
    1. Green JR, Swan CH, Gibson JA, Kerr GD, Swarbrick ET, Thornton PC. Patient-led variable dosing with balsalazide as long-term therapy for maintenance in ulcerative colitis: a 3-year prospective observational study. Alimentary Pharmacology and Therapeutics 2004;19(4):435-42. - PubMed
Hanauer 2009 {published data only}
    1. Hanauer SB, Lichtenstein GR, Kamm MA, Sandborn WJ, Lees KH, Barrett K, et al. MMX mesalamine for induction and maintenance therapy in mild-to-moderate ulcerative colitis. Gastroenterology and Hepatology 2009;5(7):494-500. - PMC - PubMed
Karamanolis 1996 {published data only}
    1. Karamanolis DG, Papatheodoridis GV, Xourgias V. Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. European Journal of Gastroenterology and Hepatology 1996;8(11):1083-8. - PubMed
Kruis 1997 {published data only}
    1. Kruis W, Schütz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 1997;11(5):853-8. - PubMed
Kruis 2004 {published data only}
    1. Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004;53(11):1617-23. - PMC - PubMed
Levine 2017 {published data only}
    1. Levine A, Yerushalmi B, Kori M, Broide E, Mozer-Glassberg Y, Shaoul R, et al. Mesalamine enemas for induction of remission in pediatric ulcerative colitis refractory to oral mesalamine: a prospective cohort study. Journal of Crohn's & Colitis 2017;11(Suppl 1):S285. - PubMed
    1. Levine A, Yerushalmi B, Kori M, Broide E, Mozer-Glassberg Y, Shaoul R. Mesalamine enemas for induction of remission in pediatric ulcerative colitis refractory to oral Mesalamine: a prospective cohort study. Journal of Pediatric Gastroenterology and Nutrition 2017;64(Suppl 1):49. - PubMed
Mani 1994 {published data only}
    1. Mani V, Gotch P. Comparison of pharmacokinetics and colonic transit time in quiescent ulcerative colitis on mesalazine and olsalazine – a cross over study. Gut 1994;35(Suppl 4):A124.
Mantzaris 2004 {published data only}
    1. Mantzaris GJ, Sfakianakis M, Archavlis E, Petraki K, Christidou A, Karagiannidis A, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. American Journal of Gastroenterology 2004;99(6):1122-8. - PubMed
Odes 1997 {published data only}
    1. Odes HS. 5-Aminosalicylic acid, 1,000-mg caplets versus 500-mg tablets, in maintenance of remission in ulcerative colitis. Journal of Clinical Gastroenterology 1997;24(4):287-8. - PubMed
Osterman 2014 {published data only}
    1. Osterman MT, Aberra F, Cross R, Liakos S, McCabe RP, Shafran I, et al. A randomized controlled trial of mesalamine dose escalation for ulcerative colitis in remission. Gastroenterology 2014;146(5 Suppl 1):S149. - PMC - PubMed
Paoluzi 2002 {published data only}
    1. Paoluzi P, D'Albasio G, Pera A, Bianchi Porro G, Paoluzi OA, Pica R, et al. Oral and topical 5-aminosalicylic acid (mesalazine) in inducing and maintaining remission in mild-moderate relapse of ulcerative colitis: one-year randomised multicentre trial. Digestive and Liver Disease 2002;34(11):787-93. - PubMed
Papatheodoridis 1995 {published data only}
    1. Papatheodoridis GV, Xourgias V, Sdonas T, Triantoafyllou M, Tzouvaia M, Karamanolis DG. Systematic load of 5-ASA in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. Gut 1995;37(Suppl 2 Pt 2):A54.
Pelech 1998 {published data only}
    1. Pelech T, Fric P, Fixa B, Komarkova O. Comparison of Mutaflor and mesalazine in the maintenance treatment of inactive ulcerative colitis. Prakticky Lekar 1998;78(10):556-8.
Pica 2015 {published data only}
    1. Pica R, Cassieri C, Cocco A, Zippi M, Marcheggiano A, De Nitto D, et al. A randomized trial comparing 4.8 vs. 2.4 g/day of oral mesalazine for maintenance of remission in ulcerative colitis. Digestive & Liver Disease 2015;47(11):933-7. - PubMed
Rubin 2017 {published data only}
    1. Rubin DT, Cohen RD, Sandborn WJ, Lichtenstein GR, Axler J, Riddell RH, et al. Budesonide multimatrix is efficacious for mesalamine-refractory, mild to moderate ulcerative colitis: a randomised, placebo-controlled trial. Journal of Crohn's & Colitis 2017;11(7):785-91. - PMC - PubMed
Scherl 2013 {published data only}
    1. Scherl E, Pruitt R, Sedghi S, Barrett A, Bortey E, Paterson C, et al. Long-term safety and tolerability of twice-daily balsalazide disodium tablets in patients with ulcerative colitis. American Journal of Gastroenterology 2013;108:S545.
Staerk Laursen 1990 {published data only}
    1. Staerk Laursen L, Stokholm M, Bukhave K, Rask-Madsen J, Lauritsen K. Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion. Gut 1990;31:1271-6. - PMC - PubMed
Stoa‐Birketvedt 1999 {published data only}
    1. Florholmen J. The systemic load and efficient delivery of active 5-ASA in patients with ulcerative colitis on treatment with Dipentum (olsalazine) and Mesasael (mesalazine). Gut 1994;35(Suppl 4):A121. - PubMed
    1. Stoa-Birketvedt G, Florholmen J. The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine. Alimentary Pharmacology and Therapeutics 1999;13:357-61. - PubMed
Sun 2016 {published data only}
    1. Sun J, Yuan Y. Mesalazine modified-release tablet in the treatment of ulcerative colitis in the remission phase: a Chinese, multicenter, single-blind, randomized controlled study. Advances in Therapy 2016;33(3):410-22. - PubMed
Tragnone 1996 {published data only}
    1. Tragnone A, Elmi G, Tagliente C, Bazzocchi G, Dina R, Euseb V, et al. Oral 5-aminosalicylic acid therapy for the prevention of relapse in patients with ulcerative colitis (UC) during remission: a new therapeutical approach by using 5-ASA tablets 800 mg. A multicenter controlled randomized trial. Gastroenterology 1996;110:A1030.
Turner 2017 {published data only}
    1. Turner D, Yerushalmi B, Kori M, Broide E, Mozer-Glassberg Y, Shaoul R, et al. Once- versus twice-daily mesalazine to induce remission in paediatric ulcerative colitis: a randomised controlled trial. Journal of Crohn's & Colitis 2017;11(5):527-33. - PubMed
Tzivras 1997 {published data only}
    1. Archimandritis A, Hatzis G, Konstandinidis A, Paraskeva K, Tjivras M, Skandalis N. Disposition of 5-ASA by olsalazine (Dipentum) and mesalazine (Asacol) in patients with ulcerative colitis in remission. Gut 1996;39(Suppl 3):A75.
    1. Tzivras M, Konstandinidis A, Hatzis G, Paraskeva K, Skandalis N, Archimandritis A. Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine. European Journal of Gastroenterology and Hepatology 1997;9(7):729-30. - PubMed
Yokoyama 2007 {published data only}
    1. Yokoyama H, Takagi S, Kuriyama S, Takahashi S, Takahashi H, Iwabuchi M, et al. Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study. Inflammatory Bowel Diseases 2007;13(9):1115-20. - PubMed
Zocco 2006 {published data only}
    1. Zocco MA, Dal Verme LZ, Cremonini F, Piscaglia AC, Nista EC, Candelli M, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 2006;23:1567-74. - PubMed

References to ongoing studies

NCT02280629 {published data only}
    1. NCT02280629. Phosphatidylcholine (LT-02) vs. placebo vs. mesalamine for maintenance of remission in ulcerative colitis (PROTECT-2) [Randomized, double-blind, double-dummy, placebo-controlled, phase III clinical trial on the efficacy and safety of a 48-weeks treatment with gastro-resistant phosphatidylcholine (LT-02) versus placebo versus mesalamine for maintenance of remission in patients with ulcerative colitis]. clinicaltrials.gov/show/NCT02280629 (first received 31 October 2014).
NCT02522780 {published data only}
    1. NCT02522780. Mesalamine 2 g Sachet for the maintenance of clinical and endoscopic remission in ulcerative colitis (UC) [A randomized, double-blind, placebo-controlled, multicenter study investigating the efficacy and safety of mesalamine 2 g extended release granules (Sachet) for maintenance of clinical and endoscopic remission in ulcerative colitis]. clinicaltrials.gov/show/NCT02522780 (first received 13 August 2015).

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