A randomized, placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn's disease. The Canadian Mesalamine for Remission of Crohn's Disease Study Group
Abstract
BACKGROUND & AIMS: The efficacy of mesalamine for the maintenance of remission in patients with Crohn's disease is controversial. The aim of this study was to conduct a double-blind, placebo-controlled study of mesalamine (750 mg four times a day for 48 weeks) in maintaining remission in 293 patients with Crohn's disease. Patients were stratified according to the method of induction of remission (medical or surgical). METHODS: Patients were assessed at weeks 4, 12, 24, 36, and 48. Relapse was defined as a Crohn's Disease Activity Index of >150 (+60 points over baseline). RESULTS: Of the 293 patients, 246 (84%) returned for at least 4 weeks of follow-up and were included in the final analysis. Thirty of the 118 (25%) who received mesalamine had a relapse compared with 47 of 128 (36%) receiving placebo (P = 0.056). Among those with relapse, the time to relapse was 119 days for the mesalamine-treated patients compared with 109 days for placebo-treated patients (P = NS). However, 25% of mesalamine-treated patients had relapsed by 249 days of follow-up compared with 154 days for placebo- treated patients. Subgroup analysis showed that patients with ileocecal- colonic disease or patients who were women had fewer relapses on mesalamine therapy than placebo-treated patients (21% vs. 41%, P = 0.018; and 19% vs. 41%, P = 0.003, respectively). CONCLUSIONS: Mesalamine treatment reduced relapse compared with placebo treatment, although conventional statistical significance was not achieved. (Gastroenterology 1997 Apr;112(4):1069-77)
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Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review
2018, Clinical Gastroenterology and HepatologyCitation Excerpt :These include relative increases in CDAI of >60 to >100 compared with baseline,94,97 as well as absolute CDAI scores of >150 to >250.75,124 Composite definitions of disease relapse were also used, with the endpoint defined by need for rescue therapy, hospitalization, or CD-related surgery.58,96,98,101,102,105–107,116–118,120,126 Fistula response and remission to therapy were defined in 6 induction and 4 maintenance RCTs.
Endpoints in randomized controlled trials (RCTs) of Crohn’s disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD.
We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication.
Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts’ Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials.
In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
A comprehensive review and update on Crohn's disease
2018, Disease-a-MonthThe term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1–20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs.
CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17–40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score.
Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or “induction therapy”, followed by maintenance of adequate response or remission, i.e. “maintenance therapy”. The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30–90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.
Comparative efficacy of pharmacologic interventions in preventing relapse of Crohn's disease after surgery: A systematic review and network meta-analysis
2015, GastroenterologyThere are several drugs that might decrease the risk of relapse of Crohn’s disease (CD) after surgery, but it is unclear whether one is superior to others. We estimated the comparative efficacy of different pharmacologic interventions for postoperative prophylaxis of CD, through a network meta-analysis of randomized controlled trials.
We conducted a systematic search of the literature through March 2014. We identified randomized controlled trials that compared the abilities of mesalamine, antibiotics, budesonide, immunomodulators, anti–tumor necrosis factor α (anti-TNF) (started within 3 months of surgery), and/or placebo or no intervention to prevent clinical and/or endoscopic relapse of CD in adults after surgical resection. We used Bayesian network meta-analysis to combine direct and indirect evidence and estimate the relative effects of treatment.
We identified 21 trials comprising 2006 participants comparing 7 treatment strategies. In a network meta-analysis, compared with placebo, mesalamine (relative risk [RR], 0.60; 95% credible interval [CrI], 0.37–0.88), antibiotics (RR, 0.26; 95% CrI, 0.08–0.61), immunomodulator monotherapy (RR, 0.36; 95% CrI, 0.17–0.63), immunomodulator with antibiotics (RR, 0.11; 95% CrI, 0.02–0.51), and anti-TNF monotherapy (RR, 0.04; 95% CrI, 0.00–0.14), but not budesonide (RR, 0.93; 95% CrI, 0.40–1.84), reduced the risk of clinical relapse. Likewise, compared with placebo, antibiotics (RR, 0.41; 95% CrI, 0.15–0.92), immunomodulator monotherapy (RR, 0.33; 95% CrI, 0.13–0.68), immunomodulator with antibiotics (RR, 0.16; 95% CrI, 0.04–0.48), and anti-TNF monotherapy (RR, 0.01; 95% CrI, 0.00–0.05), but neither mesalamine (RR, 0.67; 95% CrI, 0.39–1.08) nor budesonide (RR, 0.86; 95% CrI, 0.61–1.22), reduced the risk of endoscopic relapse. Anti-TNF monotherapy was the most effective pharmacologic intervention for postoperative prophylaxis, with large effect sizes relative to all other strategies (clinical relapse: RR, 0.02–0.20; endoscopic relapse: RR, 0.005–0.04).
Based on Bayesian network meta-analysis combining direct and indirect treatment comparisons, anti-TNF monotherapy appears to be the most effective strategy for postoperative prophylaxis for CD.
Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: A meta-analysis
2014, Digestive and Liver DiseaseSafe and effective treatments are required for patients with ulcerative colitis. It was suggested that granulocyte and monocyte adsorption apheresis might play an important role for ulcerative colitis. Therefore, a meta-analysis was performed.
Medline and the Cochrane controlled trials register were used to identify randomized controlled trials comparing granulocyte and monocyte adsorption apheresis with corticosteroids, and comparing intensive with conventional apheresis in patients with ulcerative colitis.
Nine randomized trials were eligible for inclusion criteria. According to pooled data, granulocyte and monocyte adsorption apheresis is effective for inducing clinical remission in patients with ulcerative colitis compared with corticosteroids (odds ratio, 2.23; 95% confidence interval: 1.38–3.60). However, the efficacy of granulocyte and monocyte adsorption apheresis was not dependent on the number of apheresis sessions. The intensive apheresis (≥2 sessions per week) is more effective for inducing clinical remission than weekly apheresis (odds ratio, 2.10; 95% confidence interval: 1.12–3.93). The rate of adverse events by apheresis was significantly lower than that by corticosteroids (odds ratio, 0.24; 95% confidence interval: 0.15–0.37).
Our meta-analysis reveals that intensive granulocyte and monocyte adsorption apheresis is a safe and effective treatment with higher rates of clinical remission and response for ulcerative colitis compared with corticosteroids.
A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease
2014, International Journal of SurgeryA number of agents have been evaluated in clinical trials to reduce the risk of postoperative recurrence in Crohn's disease (CD). The aim of this study was to compare the efficacy of 5-aminosalicylates, immunomodulators and biologics for postoperative prophylaxis of CD recurrence by using a network meta-analytical approach.
PubMed, Embase, and Cochrane Library were searched (update to November 2013) to identify randomized placebo-controlled, or head-to-head trials among the three drug classes for prevention of postoperative CD relapse. The primary endpoint for efficacy was endoscopic recurrence, and the secondary outcomes were clinical recurrence and adverse events. We conducted a Bayesian network meta-analysis with a mixed treatment comparisons to combine both direct and indirect evidences.
Fifteen trials involving 1507 patients were included in this analysis. Biological agents were associated with a large and significant reduction of both endoscopic and clinical recurrence compared with placebo, 5-aminosalicylates, or immunomodulators. Immunomodulators showed greater efficacy in terms of endoscopic and clinical recurrence prophylaxis compared with 5-aminosalicylates or placebo, but with higher incidence of adverse events. 5-aminosalicylates were superior to placebo for prevention of clinical recurrence, without increasing the rate of side effect.
5-aminosalicylates, immunomodulators, and biologics are more efficacious than placebo for postoperative CD prevention. Biologics are found to be the most effective medications to prevent CD recurrence.
A review on the current status and definitions of activity indices in inflammatory bowel disease: how to use indices for precise evaluation
2022, Journal of Gastroenterology