The optimal dose of 5-aminosalicylic acid in active ulcerative colitis: A dose-finding study with newly developed mesalamine

doi:10.1053/jcgh.2003.50006

Clinical Gastroenterology and Hepatology

Volume 1, Issue 1, January 2003, Pages 36-43

https://doi.org/10.1053/jcgh.2003.50006 Get rights and content

Abstract

Background & Aims: 5-Aminosalicylate is the gold standard for inducing remission in patients with mildly to moderately active ulcerative colitis. The optimal dose is as yet not defined. Despite some recent developments, the ideal formulation for 5-aminosalicylic acid is still awaited. A new pellet preparation was designed combining slow and delayed release properties. Aims of the study were to find the optimal dose and to test efficacy and safety of a new 5-aminosalicylic acid formulation. Methods: Three hundred twenty-one patients were included in a double-blind multicenter trial. Inclusion criteria were active ulcerative colitis (Clinical Activity Index [CAI] and Endoscopic Index [EI] according to Rachmilewitz, CAI 6–12; EI ≥4). Three different doses of 5-aminosalicylic acid (0.5 g 3 times a day, 1.0 g 3 times a day, and 1.5 g 3 times a day) were studied for 8 weeks. Results: Clinical remission rate (CAI ≤4) was highest in the 1.0 g 3 times a day group (66 %), 50% in the 0.5 g 3 times a day group, and 55% in the 1.5 g 3 times a day group. Hierarchical testing showed no significance, indicating a lack of dose response across the 3 mesalamine doses. In addition, times to first clinical response were similar: 26.5 days (1.0 g 3 times a day), 27.5 days (0.5 g 3 times a day), and 21.5 days (1.5 g 3 times a day). Endoscopic improvement was better with 1.0 g mesalamine 3 times a day than with 0.5 g 3 times a day, but overall endoscopic and histologic improvement was not different between treatment groups. Baseline activity, duration, and localization of ulcerative colitis did have some influence on the therapeutic activity, but there was no significant interaction with the dose of the study drug. Safety, with special focus on kidney function, was excellent in all 3 groups. Conclusions: There is no significant dose response between mesalamine 1.5 g/day, 3.0 g/day, and 4.5 g/day. The optimal dose to induce remission of ulcerative colitis is 0.5 g 5-aminosalicylic acid 3 times a day. Patients failing with this dose may benefit from an increase of the dose up to 1.0 g 3 times a day, but should also be considered for alternative treatment. A newly developed pellet formulation of 5-aminosalicylic acid has promising efficacy and excellent safety.

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2003;1:36-43

Section snippets

Patients and methods

This was a randomized, double-blind trial comparing the efficacy and safety of 3 different doses of newly developed mesalamine-containing pellets for 8 weeks in patients with mildly to moderately active UC. The study was conducted in 60 hospitals and private practice settings in Austria, Germany, Hungary, and Israel (see list of participating investigators at the end of this article).

Results

Figure 1 depicts the number of patients included and analyzed.

. Flow chart of patients included and analyzed.

Patients were well matched for demographic data and pretreatment clinical characteristics (Table 1).

. Patient characteristics at inclusion (intention-to-treat population)

Treatment group characteristic	500 mg tid	1000 mg tid	1500 mg tid
Number	103	107	106
Men	54 (52%)	56 (52%)	54 (51%)
Median age (yr, range)	39.0 (20–69)	40.0 (18–75)	41.5 (19–69)
Duration of disease (yr, mean) (SD)	7.2 (8.1)	7.7 (7.4)	7.5

Discussion

Compared to placebo, mesalamine is superior in inducing remission of UC. This effectiveness holds true for different dosage subgroups (<2 g/day, 2–2.9 g/day, ≥3 g/day), although there is a trend toward a dose-dependent relationship.² An initial dose between 1.5 g/day and 2 g/day mesalamine is widely used in clinical practice. According to clinical requirements, the dose is increased up to 4.5 g/day and more.

The present study does not demonstrate either a dose response between 3 different doses

Acknowledgements

The authors thank J. Löffler, Ph.D., medicomp Planegg, Germany, for statistical advice and L. Sallhoff, Cologne, Germany, for secreterial help.

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Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis
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We developed and validated a clinical decision support tool that has good discriminative performance for induction of endoscopic improvement in patients with mild-to-moderate UC treated with mesalamine. ClinicalTrials.gov Registration: NCT01903252.
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Citation Excerpt :
All doses of mesalamine were well tolerated, with lower rates of treatment discontinuation with active intervention compared to placebo. High-dose (6 trials, 519 patients; RR, 0.81; 95% CI, 0.71–0.92)19,39,46–49 and standard-dose mesalamine (8 trials, 906 patients; RR, 0.88; 95% CI, 0.79–0.99)39,41,42,45–50 were superior to low-dose mesalamine for induction of remission, with low heterogeneity (Supplementary Figure 2). Based on 12 trials with 2492 patients with mild–moderate UC, there was a trend favoring a small benefit of high-dose mesalamine over standard-dose mesalamine for inducing clinical remission (RR, 0.94; 95% CI, 0.88–1.01), with low heterogeneity (Supplementary Figure 3).37,39–41,46–49,51–54
Most patients with ulcerative colitis (UC) have mild-to-moderate disease activity, with low risk of colectomy, and are managed by primary care physicians or gastroenterologists. Optimal management of these patients decreases the risk of relapse and proximal disease extension, and may prevent disease progression, complications, and need for immunosuppressive therapy. With several medications (eg, sulfasalazine, diazo-bonded 5-aminosalicylates [ASA], mesalamines, and corticosteroids, including budesonide) and complex dosing formulations, regimens, and routes, to treat a disease with variable anatomic extent, there is considerable practice variability in the management of patients with mild–moderate UC. Hence, the American Gastroenterological Association prioritized clinical guidelines on this topic. To inform clinical guidelines, this technical review was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework for interventional studies. Focused questions included the following: (1) comparative effectiveness and tolerability of different oral 5-ASA therapies (sulfalsalazine vs diazo-bonded 5-ASAs vs mesalamine; low- (<2 g) vs standard (2–3 g/d) vs high-dose (>3 g/d) mesalamine); (2) comparison of different dosing regimens (once-daily vs multiple times per day dosing) and routes (oral vs rectal vs both oral and rectal); (3) role of oral budesonide in patients mild–moderate UC; (4) comparative effectiveness and tolerability of rectal 5-ASA and corticosteroid formulations in patients with distal colitis; and (5) role of alternative therapies like probiotics, curcumin, and fecal microbiota transplantation in the management of mild–moderate UC.
Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses
2018, The Lancet Gastroenterology and Hepatology
Citation Excerpt :
On active comparisons, standard-dose and high-dose mesalazine were superior to low-dose mesalazine for induction of clinical remission (appendix, p 29). High-dose mesalazine was not superior to standard-dose mesalazine (relative risk [RR] of failure to induce remission 0·94, 95% CI 0·88–1·01); however, on subgroup analysis in patients with moderate ulcerative colitis (ASCEND II,38 ASCEND III,60 Hiwatashi and colleagues39), or reporting outcomes stratified by baseline ulcerative colitis disease severity,37,41,42 high-dose mesalazine was superior to standard-dose mesalazine (six trials, 1589 patients; RR 0·92, 95% CI 0·86–0·99). Standard-dose mesalazine was not superior, whereas sulfasalazine was inferior, to diazo-bonded 5-ASAs for induction of clinical remission (appendix, p 30); balsalazide was not superior to standard-dose mesalazine (RR 0·73, 0·52–1·02).
The majority of patients with ulcerative colitis have mildly to moderately active disease. To inform the management of patients with left-sided or extensive mildly to moderately active ulcerative colitis, we assessed the comparative efficacy and tolerability of different therapies.
In this systematic review and network meta-analysis, we searched Epub, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science from inception to Dec 14, 2015, and updated on MEDLINE on March 1, 2018, for randomised controlled trials in adults (age ≥17 years) with left-sided or extensive mild to moderate ulcerative colitis. Studies were included if patients were treated with oral sulfasalazine, diazo-bonded 5-aminosalicylates (5-ASAs), mesalazine (low dose <2 g/day, standard dose 2–3 g/day, or high dose >3 g/day), controlled ileal-release budesonide, or budesonide multimatrix, alone or in combination with rectal 5-ASA therapy, and were compared with each other or placebo for induction or maintenance of clinical remission. The minimum duration of therapy was 4 weeks for trials of induction and 24 weeks for trials of maintenance therapy. We did pairwise and random-effects network meta-analysis using a frequentist approach, and calculated odds ratios (ORs) and 95% CIs; agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. We examined heterogeneity with the I² statistic.
Our search identified 1316 unique studies, from which 75 randomised trials with 12 215 patients were eligible for analysis. Based on 48 induction randomised trials (8020 participants) that met inclusion criteria, combined oral and rectal 5-ASAs (SUCRA 0·99) and high-dose mesalazine (>3 g/day; SUCRA 0·82) were ranked highest for induction of remission. Both interventions were superior to standard-dose mesalazine (2–3 g/day; failure to induce remission with combined oral and rectal 5-ASAs OR 0·41, 95% CI 0·22–0·77; high-dose mesalazine 0·78, 0·66–0·93) with moderate confidence in estimates. On the basis of 28 randomised trials (4218 participants) that met inclusion criteria, all interventions were superior to placebo for maintenance of remission; however, neither combined oral and rectal 5-ASAs nor high-dose mesalazine were superior to standard-dose mesalazine.
In patients with mildly to moderately active left-sided or extensive ulcerative colitis, combined oral and topical mesalazine therapy and high-dose mesalazine are superior to standard-dose mesalazine for induction of remission, but not maintenance of remission. Standard-dose mesalazine might be preferred for maintenance in most patients.
None.

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^☆: Address requests for reprints to: Wolfgang Kruis, M.D., Evangelisches Krankenhaus Kalk, Buchforststrasse 2, 51103 Cologne, Germany. e-mail: [email protected]; fax: (49) 221-82-89-52-91.

^☆☆: Supported by Dr. Falk Pharma GmbH, Freiburg, Germany.

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Original ArticlesThe optimal dose of 5-aminosalicylic acid in active ulcerative colitis: A dose-finding study with newly developed mesalamine☆,☆☆

Abstract

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Gastroenterol Clin North Am

Gastroenterology

Alternatives to sulfasalazine: a meta-analysis of 5-ASA in the treatment of ulcerative colitis

Inflamm Bowel Dis

Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis

Ann Intern Med

Leading article: what dose of 5-aminosalicylic acid (mesalazine) in ulcerative colitis?

Gut

Pharmacokinetics of a 5-aminosalicylic acid enteric-coated tablets and suppository dosage form

Aliment Pharmacol Ther

Gastric emptying of indigestible tablets in the relation to composition and time of ingestion of meals studied by metal detector (abstr)

Gastroenterology

Effect of food intake on gastric emptying of gastric juice-resistant tablets and capsules

Dtsch med Wschr

Coated mesalazine/5aminosalicylic acid versus sulphasalazine in the treatment of active ulcerative colitis: a randomized trial

BMJ

Microscopic activity in ulcerative colitis: what does it mean?

Gut

What predicts quality of life in Crohn's and ulcerative colitis patients? (abstr)

Gastroenterology

Original Articles
The optimal dose of 5-aminosalicylic acid in active ulcerative colitis: A dose-finding study with newly developed mesalamine☆,☆☆