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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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Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis.
Vong, C, Martin, SW, Deng, C, Xie, R, Ito, K, Su, C, Sandborn, WJ, Mukherjee, A
Clinical pharmacology in drug development. 2021;(3):229-240
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Abstract
Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (Ka ; 9.85 h-1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.
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Higher serum vitamin D levels are associated with protective serum cytokine profiles in patients with ulcerative colitis.
Gubatan, J, Mitsuhashi, S, Longhi, MS, Zenlea, T, Rosenberg, L, Robson, S, Moss, AC
Cytokine. 2018;:38-45
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BACKGROUND & AIMS Vitamin D has immune modulating effects on cytokines. Serum vitamin D levels are associated with the risk of relapse in patients with ulcerative colitis (UC), through unknown mechanisms. We tested the hypothesis that this beneficial role of vitamin D on UC is mediated through anti-inflammatory serum cytokine profiles. METHODS Serum samples from a prospective cohort of seventy UC patients in clinical remission were collected and baseline histological and endoscopic scores were recorded at enrollment. Clinical relapse events were recorded over the 12-month follow-up period. Serum vitamin D and cytokines levels (IL-6, IL-8, IL-17A, TNF-α, IFN-γ, IL-4, IL-10) were quantified using ELISA. Linear regression was used to determine correlation between vitamin D and cytokine profiles. Logistic regression models were used to determine the association between serum cytokine profiles and baseline histologic mucosal healing and clinical relapse. RESULTS Higher serum vitamin D levels positively correlated with higher ratios of IL-4 + IL-10/IL-17A + TNF-α (r = 0.37, P < .01), and IL-4 + IL-10/IL-6 + TNF-α (r = 0.32, P < .01). In multivariate analysis, IL-4 + IL-10/IL-17A + TNF-α ratios at baseline were associated with the presence of histologic mucosal healing (O.R. 1.29, 95% CI 1.02-1.62, P = .03). A higher ratio of serum IL-4 + IL-10 to IL-6 + TNF-α was associated with a reduced risk of clinical relapse (O.R. 0.72, 95% CI 0.58-0.89, P = .003), and longer time to relapse (p = .03), over the 12-month follow-up period. This ratio during remission had an AUC of 0.7 in predicting later clinical relapse. CONCLUSIONS Vitamin D is associated with anti-inflammatory serum cytokine profiles. Anti-inflammatory cytokine patterns may mediate the protective effects of higher serum vitamin D levels in patients with ulcerative colitis.
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Randomized Open-Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease Patients with Iron Deficiency.
Bokemeyer, B, Krummenerl, A, Maaser, C, Howaldt, S, Mroß, M, Mallard, N
European journal of drug metabolism and pharmacokinetics. 2017;(2):229-238
Abstract
BACKGROUND Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). Oral ferric maltol improves and normalizes hemoglobin (Hb) in patients with IBD. AIM: This open-label, randomized Phase 1 study evaluated the pharmacokinetics of ferric maltol and its effect on iron indices in IBD patients with iron deficiency (with or without anemia). METHODS Iron deficient adult IBD patients received ferric maltol 30, 60, or 90 mg twice daily during an 8-day period. Pharmacokinetics and iron uptake were assessed on days 1 and 8. RESULTS Twenty-four patients were included: 13 with Crohn's disease and 11 with ulcerative colitis (mean age 39 years; 67 % female, mean Hb 13.0 g/dL; mean reticulocyte Hb content (CHr) 31.9 pg; mean ferritin 13.9 µg/L). Plasma maltol and maltol glucuronide increased rapidly at all doses, reaching maximum plasma concentration (C max) 1.0-1.5 h post-dose and declining to baseline after 3-6 h. Maltol and maltol glucuronide exposure (area under the concentration-time curve; AUC) appeared dose proportional with twice-daily dosing, with higher exposure to maltol glucuronide vs. maltol. Mean day 8/day 1 ratios for C max and AUC0-t indicated no accumulation after 7 days of twice-daily dosing. Serum iron and transferrin saturation (TSAT) increased with all doses (maximum values at 1.5-3.0 h post-dose). Serum ferritin and CHr increased by day 8, with greater improvements with 60 and 90 mg twice-daily doses than with 30 mg twice-daily doses. CONCLUSIONS The key constituents of ferric maltol showed predictable pharmacokinetics, with no accumulation over 7 days and increased iron uptake and storage over time at 30-90 mg twice-daily doses.
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Protocol for a randomised, placebo-controlled pilot study for assessing feasibility and efficacy of faecal microbiota transplantation in a paediatric ulcerative colitis population: PediFETCh trial.
Pai, N, Popov, J
BMJ open. 2017;(8):e016698
Abstract
INTRODUCTION Ulcerative colitis (UC) is a chronic, relapsing condition characterised by colonic inflammation. Increasing prevalence in early-age diagnosis provides opportunities for additional complications in later life as a result of prolonged exposure to inflammatory and therapeutic insults, necessitating novel avenues for therapeutics which may result in fewer side effects. Faecal microbiota transplantation (FMT) has previously demonstrated potential therapeutic benefit in an adult randomised-controlled trial and several recurrent Clostridium difficile infection studies. This phase Ib pilot will be the first randomised, single-blinded, placebo-controlled trial to assess feasibility and patient outcomes in a paediatric inflammatory bowel disease (IBD) population. METHODS AND ANALYSIS Fifty patients will be randomised 1:1 to receive normal saline control or active sample. Enema administrations will be performed two times per week for 6 weeks, followed at a 6-month follow-up period. Feasibility outcomes will include measures of patient eligibility, recruitment, willingness to participate, samples collections, hospitalizations and drop-out rate. Improvements in disease symptoms will determine the efficacy of treatment. Clinical disease scores will be taken throughout the study period using the Paediatric Ulcerative Colitis Activity Index (PUCAI). Monitoring of inflammatory markers in blood and stool will be performed at regular intervals. Microbiome analysis will be conducted on stool samples collected throughout the trials period. Imaging and endoscopic surveillance will be conducted if clinically necessary. ETHICS AND DISSEMINATION Ethics was obtained from local hospital research ethics boards across all three sites. Health Canada and FDA approval was obtained for the use of an Investigatory New Drug product. Results from this trial will be presented in international conferences and published in peer-review journals. TRIAL REGISTRATION NUMBER Trial registration number: NCT02487238; preresults.
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Eldelumab [Anti-IP-10] Induction Therapy for Ulcerative Colitis: A Randomised, Placebo-Controlled, Phase 2b Study.
Sandborn, WJ, Colombel, JF, Ghosh, S, Sands, BE, Dryden, G, Hébuterne, X, Leong, RW, Bressler, B, Ullman, T, Lakatos, PL, et al
Journal of Crohn's & colitis. 2016;(4):418-28
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BACKGROUND AND AIMS Interferon-γ-inducible protein-10 [IP-10] mediates immune cell trafficking from the circulation to the inflamed colon and decreases gut epithelial cell survival. IP-10 expression is increased in patients with ulcerative colitis [UC]. We report efficacy and safety results from a dose-ranging induction study of eldelumab, a fully human monoclonal antibody to IP-10, in moderately to severely active UC. METHODS A total of 252 adults with UC [Mayo score ≥ 6 and endoscopic subscore ≥ 2] were randomised 1:1:1 to placebo or eldelumab 15 or 25 mg/kg administered intravenously on Days 1 and 8 and every other week thereafter. The primary endpoint was clinical remission [Mayo score ≤ 2; no individual subscale score > 1] at Week 11. Key secondary endpoints included Mayo score clinical response and mucosal healing at Week 11. RESULTS Neither eldelumab 15 or 25 mg/kg resulted in significant increases vs placebo in the proportion of patients achieving Week 11 clinical remission. Remission and response rates were 17.6% and 47.1% with eldelumab 25mg/kg, 13.1% and 44.0% with eldelumab 15mg/kg, and 9.6% and 31.3% with placebo. Clinical remission and response rates were higher in anti-tumour necrosis factor [TNF]-naïve patients treated with eldelumab compared with placebo. Eldelumab treatment was well tolerated and no immunogenicity was observed. CONCLUSIONS The primary endpoint was not achieved with induction treatment with eldelumab 15 or 25 mg/kg in patients with UC. Trends towards clinical remission and response were observed in the overall population and were more pronounced in anti-TNF naïve patients. Eldelumab safety signals were consistent with those reported previously [ClinicalTrials.gov number, NCT01294410].
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Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study.
Adedokun, OJ, Xu, Z, Padgett, L, Blank, M, Johanns, J, Griffiths, A, Ford, J, Zhou, H, Guzzo, C, Davis, HM, et al
Inflammatory bowel diseases. 2013;(13):2753-62
Abstract
BACKGROUND To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). METHODS This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. RESULTS Infliximab pharmacokinetics were not influenced by age (6-11 yr versus 12-17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 μg/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 μg/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 μg/mL) versus q12w (0.8 μg/mL) and with infliximab 10 mg/kg (2.9 μg/mL) versus 5 mg/kg (1.1 μg/mL) among patients who are regimen adjusted. CONCLUSIONS Infliximab pharmacokinetics/exposure-response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.
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The ileo neo rectal anastomosis: long-term results of surgical innovation in patients after ulcerative colitis and familial adenomatous polyposis.
Heikens, JT, Gooszen, HG, Teepen, JL, Hueting, WE, Oostvogel, HJ, van Vroonhoven, TJ, van Krieken, JH, van Laarhoven, CJ
International journal of colorectal disease. 2013;(1):111-8
Abstract
PURPOSE Restorative proctocolectomy with ileo neo rectal anastomosis (INRA) combines cure of ulcerative colitis (UC) or familial adenomatous polyposis (FAP) with restoration of intestinal continuity. Evaluation of long-term results was needed to determine if there is a place for INRA in the armamentarium of a surgeon besides the ileal pouch anal anastomosis (IPAA). METHODS All patients with INRA were included in the analysis. Patient demographics and clinical and follow-up data (morbidity, dietary problems, defecation frequency, fecal continence, anal and neorectal physiology, and neorectal mucosa assessment) were registered prospectively. RESULTS Seventy-nine patients were enrolled, and in 58 patients (50 UC, 8 FAP), INRA was successful. In 21 patients, intraoperative conversion to IPAA was needed. In 49 patients with INRA, a functional reservoir was achieved. No pelvic sepsis or bladder or sexual dysfunction occurred. Thirteen patients experienced episodes of reservoir inflammation. Median bowel movements of six (5, 8) with a nocturnal defecation frequency of one were recorded with fecal continence or minor incontinence. Anal manometry and neorectal physiology showed a decrease in resting pressure and an increase in squeeze pressure and maximum tolerated volume. The median follow-up was 8.1 years (6.7, 10.1). CONCLUSIONS This is an example of a surgical innovation with a theoretical potential to be superior to the current technique. This potential was not confirmed in short- and long-term evaluations. Hence, IPAA is currently the best available alternative to a conventional ileostomy.
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The effect of third-party reporting on adoption of evidence-based mesalazine regimens in ulcerative colitis: an observational study.
Kruis, W, Leifeld, L, Morgenstern, J, Pfützer, R, Reimers, B, Ceplis-Kastner, S, ,
Journal of Crohn's & colitis. 2013;(4):e125-32
Abstract
BACKGROUND AND AIMS The optimal mesalazine dosing strategy for ulcerative colitis (UC) continues to evolve. The current study aimed to explore whether documenting drug use could prompt changes in prescribing habits. METHODS In a multicenter, prospective, observational study, outpatients with active or quiescent UC were enrolled if they were receiving, or were planned to receive, sustained release mesalazine microgranules (Pentasa). Clinical and prescribing data were collected at study entry, after 2 and 8 weeks. Physician-reported influences on prescribing decisions were recorded at study entry. RESULTS 360 patients were analyzed (203 active UC, 157 remission). Prior to study entry, the range of oral mesalazine doses was 0.50-6.00 g/day in active UC patients, and 0.50-4.00 g/day for patients in remission. These changed to 1.50-5.00 g/day and 1.00-4.00 g/day, respectively, at study entry with little change thereafter. Use of a single daily mesalazine dose increased from 16.7% to 58.0% of active cases during the study, and from 5.9% to 46.8% in remission cases. Gastroenterologists reported that their basis for prescription decision-making was most frequently medical experience (80.8%), followed by guidelines (67.2%), further education or colleagues' recommendations (50.0%) and current study results (20.0%). CONCLUSION In this analysis of mesalazine dosing in routine clinical practice, there was an improvement in adherence to European Crohn's and Colitis Organisation (ECCO) guidelines and in use of once-daily dosing, consistent with recent trial results, following documentation of dosing regimens. Written reporting of drug dosing schedules should be considered fundamental for chronic, complex diseases such as UC.
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Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis.
Sandborn, WJ, Ghosh, S, Panes, J, Vranic, I, Su, C, Rousell, S, Niezychowski, W, ,
The New England journal of medicine. 2012;(7):616-24
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BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. METHODS In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. RESULTS The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. CONCLUSIONS Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).