Placebo For Maintenance Of Remission Research Articles

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

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

Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses

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.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

P-054 Probiotics for Maintenance of Remission in Ulcerative Colitis

Background: Ulcerative colitis (UC) is a chronic relapsing disease characterised by diffuse mucosal inflammation of the colon. Current maintenance treatments have multiple adverse events and an effective treatment with minimal adverse events is desired. Several studies have demonstrated the importance of intestinal flora in the pathogenesis of ulcerative colitis. It has been suggested that modifying the bacterial flora with probiotics may attenuate the inflammatory process and prevent relapses in ulcerative colitis. Five years ago, a Cochrane review found only 4 studies and no evidence regarding the efficacy of probiotics, but much work has been published in recent years. An up to date Cochrane systematic review was performed to determine the efficacy and safety of probiotics for the maintenance of remission in ulcerative colitis. Methods: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and the Cochrane Inflammatory Bowel Disease Group Specialised Trial Register were searched (Inception-January 2015). Manufacturers of probiotics were contacted to identify any unpublished trials. References of trials were also searched for any additional trials. Abstracts were considered for inclusion if full details to judge inclusion and risk of bias were offered or available from the authors. Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention for the maintenance of remission in ulcerative colitis were eligible for inclusion. Data extraction and assessment of methodological quality of included studies were independently performed by 2 authors. The main outcome measure was the occurrence of clinical or endoscopic relapse. Results: The search yielded 1006 results, with 34 papers screened in full. Seven studies (n = 887) met the inclusion criteria and were included in the review. Four trials compared probiotics to mesalazine and 3 trials compared probiotics with placebo. The studies ranged in length from 3 to 12 months. The risk of bias was low for randomisation and allocation concealment in one study and unclear in the others. One study was open label, the rest rated as low risk for blinding as double-blinded double dummy trials. The risk of bias was high in one study due to incomplete outcome data and 2 studies due to selective reporting, all the remaining studies low risk. There was no statistically significant difference between probiotics and placebo for maintenance of remission in UC, although there were just 2 small studies with 92 participants (Odds Ratio 0.56; 95% CI 0.22-1.40). Meta-analysis of 4 studies (n = 638) found no statistically significant difference between probiotics and mesalazine (OR 1.29; 95% CI 0.92-1.80). There was no statistically significant difference in the incidence of adverse events (OR 1.16; 95% CI 0.79-1.71). Conclusions: There was no statistically significant difference between probiotics and placebo, although there were just 2 small studies in the pooled analysis at some risk of bias. There was no difference in efficacy found between probiotics and mesalazine on pooled analysis and no difference in adverse events. Further research is proposed to investigate the role of probiotics to maintain remission in UC.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.

Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.

Methotrexate for maintenance of remission in Crohn's disease.

Safe and effective long-term treatments that reduce the need for corticosteroids are needed for Crohn's disease. Although purine antimetabolites are moderately effective for maintenance of remission patients often relapse despite treatment with these agents. Methotrexate may provide a safe and effective alternative to more expensive maintenance treatment with TNF-α antagonists. This review is an update of a previously published Cochrane review. To conduct a systematic review of randomized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn's disease. The Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, EMBASE, and the Cochrane IBD/FBD Group Specialized Trials Register were searched from inception to June 9, 2014. Study references and review papers were also searched for additional trials. Randomised controlled trials (RCTs) that compared methotrexate to placebo or any other active intervention for maintenance of remission in Crohn's disease were eligible for inclusion. Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients maintaining clinical remission as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the pooled risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue. Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn's disease may provide stronger evidence for the use of methotrexate in this manner.

Budesonide for maintenance of remission in Crohn's disease.

Budesonide for maintenance of remission in Crohn's disease.

Budesonide for Maintenance of Remission in Crohnʼs Disease: Update of a Systematic Review and Meta-analysis for the Cochrane Collaboration

Purpose: Budesonide (BUD) has been shown to be effective for induction of remission in Crohn's disease (CD), but concerns have been raised about the efficacy and safety of its long-term use. This systematic review and meta-analysis examined the efficacy and safety of BUD for maintenance of remission in CD. Methods: MEDLINE, EMBASE, other electronic databases, article reference lists, and conference proceedings were searched up to January, 2013 to identify randomized controlled trials on BUD. Those comparing BUD to a control treatment or comparing two doses of BUD were included. The primary outcome was maintenance of remission at one year. Secondary outcomes included mean change in CD activity index (CDAI), adverse events, and study withdrawal. Two independent investigators reviewed studies for eligibility and extracted the data. For the meta-analysis, a random or fixed effects model was chosen based on an assessment of heterogeneity. Results: Twelve studies were identified. Only one additional study was found since the previous review, which compared azathioprine with BUD. BUD 6 mg daily was no more effective than placebo for maintenance of remission at 3 months (RR 1.25, 95% CI 1.00-1.58), 6 months (RR 1.15, 95% CI 0.95-1.39), or 12 months (RR 1.13, 95% CI 0.94-1.35). BUD was neither more effective than azathioprine (RR 0.81, 95% CI 0.61-1.08), nor weaning doses of prednisolone for maintenance of remission at 12 months (RR 0.79; 95% CI 0.55-1.13), but was better than mesalamine (RR 2.51, 95% CI 1.03-6.12). BUD 3 mg daily was more effective than placebo at 3 months (RR 1.31, 95% CI 1.03-1.67). This benefit was not sustained at 6 months (RR 1.10; 95% CI 0.81-1.50), or 12 months (RR 1.04, 95% CI 0.84-1.30). The use of BUD 6 mg resulted in a modest improvement in CDAI scores at 12 months (WMD -23.49; 95% CI -46.65 to -0.32). Adverse events were more frequent in patients treated with 6 mg of BUD, compared with placebo (RR 1.49; 95% CI 1.01-2.19). Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both 6 mg daily (RR 2.88; 95% CI 1.72-4.82) and 3 mg daily (RR 2.73, 95% CI 1.34-5.57), compared with placebo. Patients receiving BUD were less likely to withdraw due to adverse events than those receiving azathioprine (RR 0.42; 95% CI 0.18-0.97). Conclusion: BUD is not more effective than placebo for maintenance of remission in CD. BUD results in a modest drop in CDAI scores; however, these benefits are offset by higher adverse events and more frequent adrenocorticoid suppression in patients receiving BUD. Lack of superiority of BUD compared to azathioprine is a new finding in this update. Disclosure - EK, AR, EIB - none. GGK - speaker for Merck, Schering-Plough, Abbott, and UCB Pharma; participated in advisory board meetings for Abbott, Merck, Schering-Plough, Shire, and UCB Pharma; research support from Abbott and Shire. ARO - advisory board for Janssen Canada, Abbvie Canada, Nestle Canada; research support (clinical trial site) from Janssen, Abbvie, Optimer US, Janssen US, Astra-Zeneca AHS - advisory boards for Merck, Abbott, and Shire; Speakers Bureau for Merck, Abbott, Shire, Aptalis, and Warner Chilcott; research support from Merck and Abbott CHS - advisory boards for Janssen Canada, Abbvie; Speaker for Janssen Canada; research support from Janssen Canada.

Role of Mesalazine in Acute and Long-Term Treatment of Ulcerative Colitis and Its Complications

Background : Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. Methods : Review of the literature. Results : The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum ® ) and balsalazide (Colazide ® Colazal ® ), and targeted release mesalazine preparations, such as Asacol ® Pentasa ® and Salofalk ® as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease, and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. Conclusion : Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.

Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study

BACKGROUND AND AIMSThe benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn's disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of...

Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial

Background & Aims: Pouchitis is the major long-term complication after ileal pouch–anal anastomosis for ulcerative colitis. Most patients have relapsing disease, and no maintenance treatment study has been performed. We evaluated the efficacy of a probiotic preparation (VSL#3) containing 5 × 1011 per gram of viable lyophilized bacteria of 4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 strain of Streptococcus salivarius subsp. thermophilus compared with placebo in maintenance of remission of chronic pouchitis. Methods: Forty patients in clinical and endoscopic remission were randomized to receive either VSL#3, 6 g/day, or an identical placebo for 9 months. Patients were assessed clinically every month and endoscopically and histologically every 2 months or in the case of a relapse. Fecal samples were collected for stool culture before and after antibiotic treatment and each month during maintenance treatment. Results: Three patients (15%) in the VSL#3 group had relapses within the 9-month follow-up period, compared with 20 (100%) in the placebo group (P < 0.001). Fecal concentration of lactobacilli, bifidobacteria, and S. thermophilus increased significantly from baseline levels only in the VSL#3-treated group (P < 0.01). Conclusions: These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic pouchitis.GASTROENTEROLOGY 2000;119:305-309