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Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial.
Peyrin-Biroulet, L, Hart, A, Bossuyt, P, Long, M, Allez, M, Juillerat, P, Armuzzi, A, Loftus, EV, Ostad-Saffari, E, Scalori, A, et al
The lancet. Gastroenterology & hepatology. 2022;(2):128-140
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Abstract
BACKGROUND Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. METHODS HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov, NCT02100696. FINDINGS HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). INTERPRETATION HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. FUNDING F Hoffmann-La Roche.
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Effects of saffron supplementation on oxidative/antioxidant status and severity of disease in ulcerative colitis patients: A randomized, double-blind, placebo-controlled study.
Tahvilian, N, Masoodi, M, Faghihi Kashani, A, Vafa, M, Aryaeian, N, Heydarian, A, Hosseini, A, Moradi, N, Farsi, F
Phytotherapy research : PTR. 2021;(2):946-953
Abstract
Supplementation with saffron helps improve antioxidant status. Oxidative stress plays an important role in ulcerative colitis (UC). The present study aimed to investigate the effect of saffron supplementation on disease severity and Oxidative/Antioxidant factors in patients with UC. This randomized double-blinded study was conducted on 80 mild to moderate UC patients. Participants were randomly divided into intervention (100 mg saffron/daily) and placebo (100 mg maltodextrin/daily) groups. Of all the participants, 75 completed the study. After 8 weeks, there were significantly increased in the mean score of simple clinical colitis activity index questionnaire (3.83 ± 1.78 to 3 ± 1.60, p = .004), the serum levels of total antioxidant capacity (2.68 ± 0.90 to 2.79 ± 0.87, p = .016), superoxide dismutase (60.69 ± 9.59 to 66.30 ± 10.79, p = .009) and glutathione peroxidase (22.05 ± 14.27 to 29.67 ± 17.97, p = .011) in patients received saffron compared to the placebo group. Whereas, there was no significant difference in serum levels of malondialdehyde between the two groups. Finally, dietary saffron as an alternative therapy may effective in improving antioxidant factors and reducing the severity of disease in UC patients.
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Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials.
Panaccione, R, Isaacs, JD, Chen, LA, Wang, W, Marren, A, Kwok, K, Wang, L, Chan, G, Su, C
Digestive diseases and sciences. 2021;(8):2732-2743
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Abstract
BACKGROUND Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated. METHODS Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization. RESULTS Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies. CONCLUSIONS In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases. TRIAL REGISTRATION NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.
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Oral Sucrosomial Iron Is as Effective as Intravenous Ferric Carboxy-Maltose in Treating Anemia in Patients with Ulcerative Colitis.
Bertani, L, Tricò, D, Zanzi, F, Baiano Svizzero, G, Coppini, F, de Bortoli, N, Bellini, M, Antonioli, L, Blandizzi, C, Marchi, S
Nutrients. 2021;(2)
Abstract
Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy-maltose (FCM) in patients with ulcerative colitis in remission and mild-to-moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment-by-time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment-by-time interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild-to-moderate anemia in patients with ulcerative colitis under remission.
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The effect of a mindfulness-based therapy on different biomarkers among patients with inflammatory bowel disease: a randomised controlled trial.
González-Moret, R, Cebolla, A, Cortés, X, Baños, RM, Navarrete, J, de la Rubia, JE, Lisón, JF, Soria, JM
Scientific reports. 2020;(1):6071
Abstract
Mindfulness-based interventions have shown some efficacy in decreasing stress levels and improving quality of life. However, so far, only a few studies have studied this type of intervention among patients with inflammatory bowel disease and none of them have studied their effects on inflammatory biomarkers. This current study was a two-armed, single-centre, randomised (2:1 ratio) controlled trial used to evaluate the effects of a mindfulness-based intervention (n = 37) compared to standard medical therapy (n = 20) in patients with Crohn's disease or ulcerative colitis. The mindfulness intervention blended four internet-based therapy modules with four face-to-face support sessions. The outcomes we assessed were faecal calprotectin (primary outcome), C-reactive protein, and cortisol levels measured in hair samples at several timepoints. The between-group analysis highlighted significant decreases in faecal calprotectin and in C-reactive protein levels in the mindfulness-based intervention group compared to the standard medical therapy group at the six-month follow-up (faecal calprotectin: -367, [95% CI: -705, -29], P = 0.03; C-reactive protein: -2.82, [95% CI: -5.70, 0.08], P = 0.05), with moderate to large effect sizes (faecal calprotectin: ηp2 = 0.085; C-reactive protein: ηp2 = 0.066). We concluded that mindfulness-based therapy administered as part of standard clinical practice effectively improves inflammatory biomarkers in patients diagnosed with inflammatory bowel disease.
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The effect of curcumin supplementation on clinical outcomes and inflammatory markers in patients with ulcerative colitis.
Sadeghi, N, Mansoori, A, Shayesteh, A, Hashemi, SJ
Phytotherapy research : PTR. 2020;(5):1123-1133
Abstract
BACKGROUND AND AIMS Curcumin has anti-inflammatory properties. The aim of this study was to evaluate the effect of curcumin on improvement of the disease activity in ulcerative colitis (UC). METHODS In this randomized double-blind clinical trial, 70 patients with mild-to-moderate UC were randomly assigned to curcumin (1,500 mg/day) or placebo intake for 8 weeks. Disease clinical activity, quality of life, serum levels of tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR) values, and complete blood count were measured. RESULTS Changes in Simple Clinical Colitis Activity Index score were significantly higher in the curcumin than the placebo group (-5.9 ± 2.08 vs. -2.1 ± 2.6; p = .001). The scores of Inflammatory Bowel Disease Questionnaire-9 and quality of life were significantly higher in the intervention group compared to the control group (p = .006). Furthermore, the curcumin supplementation reduced the serum hs-CRP concentration (-6.3 ± 13.6 vs. 3.7 ± 11.6 μg/ml; p = .01) and ESR levels significantly (-1.6 ± 2.7 vs. -0.09 ± 2.4 mm/hr; p = .02) in comparison with the control group. No significant changes were observed in the TNF-α levels of both groups. CONCLUSIONS Consumption of the curcumin supplement, along with drug therapy, is associated with significant improvement of the clinical outcomes, quality of life, hs-CRP, and ESR in patients with mild-to-moderate UC.
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Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial.
Sharifi, A, Vahedi, H, Nedjat, S, Rafiei, H, Hosseinzadeh-Attar, MJ
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2019;(10):681-687
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon. It has been proposed that the UC pathogenesis may be related to vitamin D deficiency and/or vitamin D administration in UC patients may have an ameliorating effect on the intestinal inflammation. The aim of this study was to assess the effect of vitamin D on the serum levels of immune cytokines in UC patients. In this double-blind randomized controlled trial, 90 mild-to-moderate UC patients were assigned to get either a single muscular injection of 7.5 mg vitamin D3 or 1 mL normal saline as placebo. Three months later serum levels of IL-4, IL-10, IL-12p70, IFN-γ, and TNF-α were measured. Two group variables were compared using independent t-test and analysis of covariance (ANCOVA). There was a significant increase in vitamin D only in the vitamin D group. Compared to placebo, vitamin D had significant decreasing effects on serum TNF-α, IFN-γ, and IL12p70 levels, but it had no significant effect on serum levels of IL4 and IL10. Vitamin D seems to inhibit Th1 immune responses and have no effect on Th2 responses. The findings of this study support several in vitro studies, which suggest a therapeutic immunomodulatory potential of vitamin D.
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Vitamin D Decreases Beck Depression Inventory Score in Patients with Mild to Moderate Ulcerative Colitis: A Double-Blind Randomized Placebo-Controlled Trial.
Sharifi, A, Vahedi, H, Nedjat, S, Mohamadkhani, A, Hosseinzadeh Attar, MJ
Journal of dietary supplements. 2019;(5):541-549
Abstract
The prevalence of depression in inflammatory bowel disease (IBD) is significantly more than in controls. Some studies assessed the link between vitamin D and depression. The aim of this study was to assess the effect of vitamin D on Beck Depression Inventory (BDI) score in ulcerative colitis (UC) patients. In this double-blind randomized controlled trial, 90 mild to moderate UC patients were assigned to receive a single injection of 300,000 IU vitamin D3 or 1 ml normal saline as placebo. At baseline and 3 months later, measurements of BDI score and serum 25-OH-vitamin D3 were done. Data were compared by independent sample t test, Mann-Whitney U test, and analysis of covariance (ANCOVA). Baseline BDI scores were not statistically different between the two groups (p = .4); scores decreased in the vitamin D group after the intervention (p = .023). Further subgroup analysis regarding baseline serum vitamin D levels and adjusted for baseline BDIs revealed lowering effect of vitamin D on BDI scores only in subgroup with baseline serum vitamin D levels equal to or higher than 30 ng/ml (p < .001). In this study, there was a statistically significant reduction in BDI score in mild to moderate UC patients 3 months after 300,000 IU vitamin D3 injection. Subgroup analysis showed that patients with sufficient baseline vitamin D may benefit from supplementation more than vitamin D-deficient patients, which indicates that higher serum vitamin D levels may be needed for its antidepressant effect.
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Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial.
Costello, SP, Hughes, PA, Waters, O, Bryant, RV, Vincent, AD, Blatchford, P, Katsikeros, R, Makanyanga, J, Campaniello, MA, Mavrangelos, C, et al
JAMA. 2019;(2):156-164
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Abstract
IMPORTANCE High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity. OBJECTIVE To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool. DESIGN, SETTING, AND PARTICIPANTS A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017. INTERVENTIONS Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months. MAIN OUTCOMES AND MEASURES The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. RESULTS Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group. CONCLUSIONS AND RELEVANCE In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12613000236796.
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The efficacy of curcuminoids in improvement of ulcerative colitis symptoms and patients' self-reported well-being: A randomized double-blind controlled trial.
Masoodi, M, Mahdiabadi, MA, Mokhtare, M, Agah, S, Kashani, AHF, Rezadoost, AM, Sabzikarian, M, Talebi, A, Sahebkar, A
Journal of cellular biochemistry. 2018;(11):9552-9559
Abstract
BACKGROUND Curcuminoids are polyphenols with documented anti-inflammatory activity and has been shown to improve the symptoms of several inflammatory diseases. We aimed to evaluate the effectiveness of a nanoformulation of curcuminoids in the treatment of ulcerative colitis. METHODS This randomized double-blinded controlled trial was conducted on 56 patients aged 18 years or older with the final diagnosis of mild to moderate ulcerative colitis according to the Simple Clinical Colitis Activity Index (SCCAI). The patients were randomly assigned (using a computerized random sampling table) to receive curcuminoids nanomicelles (80 mg, three times daily, orally) plus mesalamine (3 g/24 hours, orally) as the treatment group and placebo plus mesalamine (3 g/24 hours, orally) as the control group for a period of four weeks. The severity of disease was assessed at baseline and at the end of the second and fourth weeks of the treatment according to the SCCAI. RESULTS The score for urgency of defecation reduced significantly more in case group as compared with control group at four weeks after beginning the treatment. The patients in case group experienced better general condition than the control ones after 4 weeks of treatment. Overall, the mean SCCAI score was significantly lower in the patients received curcuminoids nanomicelles plus mesalamine as compared with the group received placebo plus mesalamine at fourth week after the treatment (1.71 ± 1.84 vs 2.68 ± 2.09, p = 0.050). CONCLUSION Adding curcuminoids nanomicelles to routine treatment of patients with ulcerative colitis is associated with a significant improvement of symptoms, including reduced frequency of urgent defecation, improved patients' self-reported well-being and reduced clinical activity of ulcerative colitis. ClinicalTrials. "IRCT2017052634142N1".