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First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.
Jongsma, MME, Aardoom, MA, Cozijnsen, MA, van Pieterson, M, de Meij, T, Groeneweg, M, Norbruis, OF, Wolters, VM, van Wering, HM, Hojsak, I, et al
Gut. 2022;(1):34-42
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Abstract
OBJECTIVE In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Registry (NCT02517684).
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Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.
Schreiber, S, Ben-Horin, S, Leszczyszyn, J, Dudkowiak, R, Lahat, A, Gawdis-Wojnarska, B, Pukitis, A, Horynski, M, Farkas, K, Kierkus, J, et al
Gastroenterology. 2021;(7):2340-2353
Abstract
BACKGROUND & AIMS This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.
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Citrulline correlations in short bowel syndrome-intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study.
Jeppesen, PB, Gabe, SM, Seidner, DL, Lee, HM, Olivier, C
Clinical nutrition (Edinburgh, Scotland). 2020;(8):2479-2486
Abstract
BACKGROUND & AIMS Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. METHODS A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. RESULTS Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo. CONCLUSION Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.
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Maintenance of Remission Among Patients With Inflammatory Bowel Disease After Vedolizumab Discontinuation: A Multicentre Cohort Study.
Martin, A, Nachury, M, Peyrin-Biroulet, L, Bouhnik, Y, Nancey, S, Bourrier, A, Serrero, M, Fumery, M, Buisson, A, Laharie, D, et al
Journal of Crohn's & colitis. 2020;(7):896-903
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Abstract
BACKGROUND AND AIM It is unclear whether vedolizumab therapy can be discontinued in patients with inflammatory bowel disease [IBD] after achieving steroid-free clinical remission. The aim was to assess the risk of relapse after vedolizumab therapy was discontinued. METHODS This was a retrospective observational study, collecting data from 21 tertiary centres affiliated with the GETAID from January 2017 to April 2019. Consecutive patients with IBD, who were in steroid-free clinical remission for at least 3 months and were treated with vedolizumab for at least 6 months, were included at the time of vedolizumab discontinuation. RESULTS A total of 95 patients [58 with Crohn's disease] discontinued vedolizumab after a median duration of therapy of 17.5 [10.6-25.4] months. After a median follow-up period of 11.2 [5.8-17.7] months, 61 [64%] patients experienced disease relapse. The probabilities of relapse-free survival were 83%, 59%, and 36% at 6, 12, and 18 months, respectively. According to the multivariate analysis, a C-reactive protein level less than 5 mg/L at vedolizumab discontinuation (hazard ratio [HR] = 0.56, 95% confidence interval [CI] [0.33-0.95], p = 0.03) and discontinuation due to patients' elective choice (HR = 0.41, 95% CI [0.21-0.80], p = 0.009) were significantly associated with a lower risk of relapse. Re-treatment with vedolizumab was noted in 24 patients and provided steroid-free clinical remission in 71% and 62.5% at Week 14 and after a median follow-up of 11.0 [5.4-13.3] months, respectively, without any infusion reactions. CONCLUSIONS In this retrospective study, two-thirds of patients with IBD treated with vedolizumab experienced relapse within the first year after vedolizumab discontinuation. Re-treatment with vedolizumab was effective in two-thirds of patients.
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Six-month outcomes of teduglutide treatment in adult patients with short bowel syndrome with chronic intestinal failure: A real-world French observational cohort study.
Joly, F, Seguy, D, Nuzzo, A, Chambrier, C, Beau, P, Poullenot, F, Thibault, R, Armengol Debeir, L, Layec, S, Boehm, V, et al
Clinical nutrition (Edinburgh, Scotland). 2020;(9):2856-2862
Abstract
BACKGROUND & AIMS Teduglutide, a GLP-2-analog, has proven effective in two placebo-controlled studies in reducing parenteral support (PS) in patients with short bowel syndrome-associated intestinal failure (SBS-IF) after 24 weeks. The aim of this study was to describe in a real-life situation the effects of teduglutide treatment and their predictive factors. METHODS We included 54 consecutive SBS-IF patients treated with teduglutide in France for at least 6 months from 10 expert centers. Small bowel length was 62 ± 6 cm and 65% had colon in continuity. PS was 4.4 ±0 .2 infusions per week, started 9.8 ± 1.2 years before. Response (PS reduction ≥ 20%) and PS discontinuation rates were assessed at week 24. Adjusted p values of factors associated with response and weaning were calculated using a multivariate logistic regression model. RESULTS At week 24, 85% of patients were responders and 24% had been weaned off PS, with a 51% reduction of PS needs and 1.5 ± 0.2 days off PS per week. Response to teduglutide was influenced by a higher baseline oral intake (p = 0.02). Weaning off PS was influenced by the presence of colon (p = 0.04), a lower PS volume (p = 0.03) and a higher oral intake (p = 0.01). There were no differences based on age, bowel length or SBS-IF causes. CONCLUSIONS Our study confirms the effectiveness of teduglutide in reducing PS needs in SBS-IF patients. We associated reduced parenteral support volume with baseline parenteral volume support, bowel anatomy, and oral intake. These findings underline the role of nutritional optimization when starting the treatment.
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Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.
Wang, JY, Bajaj, JS, Wang, JB, Shang, J, Zhou, XM, Guo, XL, Zhu, X, Meng, LN, Jiang, HX, Mi, YQ, et al
Journal of digestive diseases. 2019;(10):547-556
Abstract
OBJECTIVE Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. METHODS This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. RESULTS A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. CONCLUSIONS Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).
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Vedolizumab Therapy is Ineffective for Primary Sclerosing Cholangitis in Patients With Inflammatory Bowel Disease: A GETAID Multicentre Cohort Study.
Caron, B, Peyrin-Biroulet, L, Pariente, B, Bouhnik, Y, Seksik, P, Bouguen, G, Caillo, L, Laharie, D, Carbonnel, F, Altwegg, R, et al
Journal of Crohn's & colitis. 2019;(10):1239-1247
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Abstract
BACKGROUND Whether vedolizumab may be effective as a treatment for primary sclerosing cholangitis [PSC] in patients with inflammatory bowel disease [IBD] remains controversial. METHODS We performed a retrospective observational study of consecutive patients with IBD and PSC, treated with vedolizumab for at least 30 weeks in 22 centres of GETAID from January 2015 to June 2016. The outcomes included a decrease in the serum alkaline phosphatase [ALP] concentration of at least 50% from baseline to Week 30 or 54, a change in any serum liver enzymes concentrations, and an assessment of the efficacy and safety of vedolizumab in IBD. RESULTS Among 75 patients with active IBD and PSC treated with vedolizumab, 21 patients discontinued vedolizumab before Week 30 [due to lack of efficacy in 19 and malignancy in two patients]. In the remaining 54 patients, a decrease in the serum ALP concentration of at least 50% from baseline to Weeks 30 and 54 was observed in four [7%] and four [11%] patients, respectively. No significant change was observed in serum liver enzyme concentrations at week 30 or 54. After a median follow-up period of 19.4 [14.0-29.9] months, nine cases of digestive neoplasia [colorectal neoplasia in seven and cholangiocarcinoma in two] were reported. CONCLUSIONS In patients with IBD and PSC, vedolizumab did not improve serum liver enzyme concentrations at week 30 or 54. Nine cases of digestive cancer occurred during the follow-up period, confirming the need for a tight surveillance programme in this population.
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Erythromycin versus metoclopramide for post-pyloric spiral nasoenteric tube placement: a randomized non-inferiority trial.
Hu, B, Ouyang, X, Lei, L, Sun, C, Chi, R, Guo, J, Guo, W, Zhang, Y, Li, Y, Huang, D, et al
Intensive care medicine. 2018;(12):2174-2182
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Abstract
PURPOSE To determine whether erythromycin is non-inferior to metoclopramide in facilitating post-pyloric placement of self-propelled spiral nasoenteric tubes (NETs) in critically ill patients. METHODS A prospective, multicenter, open-label, parallel, and non-inferiority randomized controlled trial was conducted comparing erythromycin with metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients admitted to intensive care units (ICUs) of eight tertiary hospitals in China. The primary outcome was procedure success defined as post-pyloric placement (spiral NETs reached the first portion of the duodenum or beyond confirmed by abdominal radiography 24 h after tube insertion). RESULTS A total of 5688 patients were admitted to the ICUs. Of these, in 355 patients there was a plan to insert a nasoenteric feeding tube, of whom 332 were randomized, with 167 patients assigned to the erythromycin group and 165 patients assigned to the metoclopramide group. The success rate of post-pyloric placement was 57.5% (96/167) in the erythromycin group, as compared with 50.3% (83/165) in the metoclopramide group (a difference of 7.2%, 95% CI - 3.5% to 17.9%), in the intention-to-treat analysis, not including the prespecified margin of - 10% for non-inferiority. The success rates of post-D1 (reaching the second portion of the duodenum or beyond), post-D2 (reaching the third portion of the duodenum or beyond), post-D3 (reaching the fourth portion of the duodenum or beyond), and proximal jejunum placement and the incidence of any adverse events were not significantly different between the groups. CONCLUSIONS Erythromycin is non-inferior to metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients. The success rates of post-D1, post-D2, post-D3, and proximal jejunum placement were not significantly different.
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Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.
Kulke, MH, Hörsch, D, Caplin, ME, Anthony, LB, Bergsland, E, Öberg, K, Welin, S, Warner, RR, Lombard-Bohas, C, Kunz, PL, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(1):14-23
Abstract
Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.
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Independence From Parenteral Nutrition and Intravenous Fluid Support During Treatment With Teduglutide Among Patients With Intestinal Failure Associated With Short Bowel Syndrome.
Iyer, KR, Kunecki, M, Boullata, JI, Fujioka, K, Joly, F, Gabe, S, Pape, UF, Schneider, SM, Virgili Casas, MN, Ziegler, TR, et al
JPEN. Journal of parenteral and enteral nutrition. 2017;(6):946-951
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Abstract
BACKGROUND In phase III clinical studies, treatment with teduglutide was associated with clinically meaningful reductions (≥20% from baseline) in parenteral support (PS; parenteral nutrition and/or intravenous fluids) requirements in adult patients with intestinal failure associated with short bowel syndrome (SBS-IF). This analysis reports clinical characteristics of patients who achieved complete independence from PS during teduglutide treatment. MATERIALS AND METHODS Post hoc analysis of adult patients who achieved complete PS independence during treatment with teduglutide 0.05 mg/kg/d. Data were pooled from 5 teduglutide clinical trials (2 phase III placebo-controlled trials [NCT00081458 and NCT00798967] and their respective extension studies [NCT00172185, NCT00930644, NCT01560403]). Descriptive statistics were used; no between-group comparisons were performed because of the small sample size and lack of comparator. RESULTS Of 134 patients, 16 gained oral or enteral autonomy after a median of 5 years of PS dependence and 89 weeks of teduglutide treatment. Demographic and baseline disease characteristics varied among patients (median age, 55 years; 50% men; median baseline PS volume, 5.1 L/wk; median residual small intestine length, 52.5 cm). Most patients who achieved PS independence had colon-in-continuity; however, there was no significant difference in the frequency of PS independence among patients who maintained colon-in-continuity vs those who did not. CONCLUSION Findings from this post hoc analysis suggest that oral or enteral autonomy is possible for some patients with SBS-IF who are treated with teduglutide, regardless of baseline characteristics and despite long-term PS dependence.