Etrasimod for the Treatment of Ulcerative Colitis: Up to 2.5 Years of Pooled Safety Data From Global Clinical Trials
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PROVIDER: S-EPMC10910369 | biostudies-literature | 2023 Jul
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Project description:Background and aimsPreviously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn's disease [CD] and 4 years in ulcerative colitis [UC].MethodsIn phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals.ResultsIn this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported.ConclusionThe final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications.Clinical trials.gov numbersNCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236.
| S-EPMC11302965 | biostudies-literature
Project description:Background and aimsTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report an integrated summary of tofacitinib safety from the completed global UC clinical program (9.2 years maximum tofacitinib exposure).MethodsThis analysis included patients receiving tofacitinib 5 or 10 mg twice daily (b.i.d.) from completed phase 2/3 placebo-controlled studies, an open-label, long-term extension study and a randomized phase 3b/4 study. Proportions and incidence rates (IRs; unique patients with events/100 patient-years [PY] of exposure) were evaluated for deaths and adverse events (AEs) of special interest (AESI).ResultsOverall, 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg b.i.d.; 938 (81.1%) were in the predominant dose tofacitinib 10 mg b.i.d. group; 552 (47.7%) received tofacitinib for ≥2 years; total exposure: 3202.0 PY; 994 (85.9%) experienced AEs; 254 (22.0%) experienced serious AEs. Median treatment duration: 1.7 (range 0.0-9.2) years. IRs (95% CI) for combined tofacitinib doses: deaths 0.24 (0.10-0.48); serious infections (SIs) 1.80 (1.37-2.32); herpes zoster (HZ; non-serious and serious) 3.24 (2.63-3.94); serious HZ 0.24 (0.10-0.48); opportunistic infections 0.96 (0.65-1.36); malignancies (excluding non-melanoma skin cancer [NMSC]) 0.88 (0.59-1.26); NMSC 0.71 (0.45-1.07); major adverse cardiovascular events 0.27 (0.12-0.52); deep vein thrombosis 0.06 (0.01-0.22); pulmonary embolism 0.18 (0.07-0.40); and gastrointestinal perforations 0.09 (0.02-0.27).ConclusionsExcept for HZ and SIs, IRs for AESI were <1 case/100 PY. Safety was consistent with previous analyses of shorter exposure and tofacitinib's known safety profile, including real-world data.ClinicaltrialsGOV: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT03281304.
| S-EPMC11249803 | biostudies-literature
Project description:Background and aimsTofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme.MethodsPatients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated.ResultsIn total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09-0.46]; serious infections, 1.69 [1.26-2.21]; herpes zoster [non-serious and serious], 3.30 [2.67-4.04]; opportunistic infections, 1.03 [0.70-1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55-1.24]; NMSC, 0.73 [0.45-1.10]; MACE, 0.29 [0.13-0.55]; deep vein thrombosis, 0.03 [0.00-0.18]; pulmonary embolism, 0.19 [0.07-0.42]; gastrointestinal perforations, 0.10 [0.02-0.28].ConclusionsAESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 [2020] Cohort, with the exception of herpes zoster [a known risk of tofacitinib treatment]. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304JCC Topic/keyword selection: 3. Clinical trials.
| S-EPMC10069618 | biostudies-literature
Project description:Background and aimsEtrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks.MethodsIn OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks.ResultsIn all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients.ConclusionsIn this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.
| S-EPMC8218705 | biostudies-literature
Project description:ObjectiveEtrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P1 receptor expression on cardiac cells is involved in cardiac conduction. We report cardiovascular treatment-emergent adverse events (TEAEs) associated with S1P receptor modulators and other cardiovascular events in the etrasimod UC clinical programme.MethodsPatients were analysed in the Placebo-controlled UC cohort and All UC cohort. Incidence rates (IRs, per 100 patient-years) of cardiovascular-related TEAEs associated with S1P receptor modulators, including bradycardia/atrioventricular (AV) block and hypertension, and other cardiovascular events, including coronary artery disease (CAD) and cerebrovascular disease (CVD), were analysed.ResultsIn patients receiving etrasimod, cardiovascular-related TEAEs were infrequent (≤2.6% per AE). In the Placebo-controlled UC cohort, IRs (95% CIs) for cardiovascular-related TEAEs were higher for patients receiving etrasimod (n=577) vs placebo (n=314), respectively, for bradycardia/sinus bradycardia, 3.85 (1.58 to 6.13) vs 0 and AV block, 1.40 (0.03 to 2.76) vs 0; and numerically higher for hypertension, 5.31 (2.62 to 7.99) vs 3.40 (0.07 to 6.72). Most bradycardia/AV block events were reported on day 1. All bradycardia and hypertension TEAEs were non-serious. One serious second-degree AV block type 1 TEAE occurred in the etrasimod group; no events of second-degree AV block type 2 or higher were reported. One event each of CAD and CVD occurred in two patients receiving etrasimod.ConclusionsIn the etrasimod UC clinical programme, IRs of cardiovascular-related TEAEs and other cardiovascular events were low. Most cardiovascular-related TEAEs were non-serious.Trial registration numbersNCT02447302; NCT03945188; NCT03996369; NCT02536404; NCT03950232; NCT04176588.
| S-EPMC11748931 | biostudies-literature
Project description:Background and aimsInfections are a safety concern in patients with ulcerative colitis [UC]. Etrasimod is an oral, once daily [QD], selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE programme.MethodsProportions, incidence rates [IRs; per 100 patient-years], and descriptive analyses of all serious, severe, herpes zoster and opportunistic infections are reported in the Pivotal UC cohort [ELEVATE UC 52 and ELEVATE UC 12]. Cox regression models evaluated potential baseline risk factors.ResultsIn this analysis [n = 787], proportions [IRs] of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three [0.6%] and five [1.9%] patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group [etrasimod: 0.4%; placebo: 0.8%], all localised and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count [ALC] < 0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred.ConclusionsPatients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC < 0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterise the etrasimod safety profile. Clinicaltrials.gov: NCT03945188; NCT03996369.
| S-EPMC11479712 | biostudies-literature
Project description:Background and aimsCumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined.MethodsData from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9 mg, 6 mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9 mg or placebo for 4 weeks, then open-label budesonide MMX 9 mg for 4 weeks]; and one open-label study [budesonide MMX 9 mg for 8 weeks] were pooled.ResultsPatients randomised to budesonide MMX 9 mg [n = 288], 6 mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9 mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects.ConclusionsBudesonide MMX 9 mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.
| S-EPMC4736820 | biostudies-literature
Project description:Background and aimsThe UNIFI long-term extension [LTE] study reports the efficacy and safety of subcutaneous 90 mg ustekinumab through 3 years of maintenance therapy.MethodsPatients randomised to ustekinumab every 12 weeks [q12w] or every 8 weeks [q8w] at maintenance baseline [N = 348] and randomised ustekinumab-treated patients in the LTE [N = 284] were evaluated. Symptomatic remission [Mayo stool frequency = 0/1, rectal bleeding = 0] was assessed. Safety included all LTE patients [N = 188 placebo and N = 457 ustekinumab].ResultsAmong patients randomised to the ustekinumab q12w and q8w groups at maintenance baseline, 54.1% and 56.3% achieved symptomatic remission at Week 152, respectively. Overall, 20% of patients discontinued ustekinumab, 10% of biologic-naïve and 30% of biologic-exposed patients. Among patients in symptomatic remission at Year 3, 94.6% and 98.0% of patients were also corticosteroid free, respectively. Corticosteroid-free symptomatic remission rates in the ustekinumab q12w and q8w groups were 51.2% and 55.1% at Week 152, respectively. Remission rates were higher for biologic-naïve patients than for those with a history of biologic failure. Biochemical evidence of response was demonstrated by stable, decreased C-reactive protein and faecal calprotectin measurements over 3 years. From Weeks 96 to 156, no deaths, major adverse cardiovascular events, or tuberculosis occurred. Nasopharyngitis, ulcerative colitis, and upper respiratory tract infection were most frequently reported. One ustekinumab-treated patient with a history of basal cell carcinoma [BCC] reported two BCCs. One patient in the q8w ustekinumab group, who was receiving concomitant 6-mercaptopurine, experienced serious adverse events of neutropenic sepsis and oral herpes.ConclusionsEfficacy of ustekinumab in patients with ulcerative colitis was confirmed through 3 years. No new safety signals were observed.
| S-EPMC9426670 | biostudies-literature
Project description:Background and aimUlcerative colitis is a chronic inflammatory bowel disease, and intestinal flora plays an important role in ulcerative colitis. In this study, we conducted a bibliometric analysis of publications in the field of intestinal flora and ulcerative colitis research in the past 10 years to summarize the current status of the field and analyze the trends in the field.MethodsOn July 15, 2022, we chose the Web of Science Core Collection database as the study's data source. CiteSpace.5.8.R3 and VOSviewer 1.6.17 were used to examine publications of research on intestinal flora and ulcerative colitis that were published between 2012 and 2021. We looked through the papers for journals, organizations, nations and regions, authors, and key terms.ResultsThis analysis covered a total of 2,763 papers on studies into intestinal flora and ulcerative colitis. There were 13,913 authors, 93 nations, 3,069 organizations, and 759 journals in all of the articles. In the USA, 767 publications were the most. The university with the most publications was Harvard Medical School. The author with the most articles was Antonio Gasbarrini.ConclusionThis study summarizes the global research trends in intestinal flora and ulcerative colitis. Publications in this field have increased year by year in the last decade and the field of research on intestinal flora and ulcerative colitis has good prospects for growth.
| S-EPMC9490179 | biostudies-literature
Project description:BackgroundThe Ulcerative Colitis (UC) Narrative is a global patient and physician survey aimed at identifying the impact of UC and comparing and contrasting perceptions of UC burden and management approaches.MethodsSurveys of patients with UC (self-reported diagnosis; n = 2100) and physicians (n = 1254) were completed across 10 countries by The Harris Poll between August 2017 and February 2018. Questionnaires covered multiple aspects of UC, including diagnosis, treatment, and impact on patient quality of life, in addition to standard demographic information. Descriptive statistics are reported.ResultsThe majority of patients (82%) had moderate to severe UC (based on medication history; those who had only ever taken 5-aminosalicylates were excluded); 67% described their UC as controlled with few to no symptoms. On average, patients experienced 4.3 flares (standard deviation, 7.4) in the past year. Diagnostic delay was on average 2.0 years (standard deviation, 5.4); 42% of patients waited ≥1 year. Most patients (65%) felt that UC controlled their life rather than them controlling their disease. Because of the fear of repercussions, many patients had not disclosed their UC to their employer. Discussion of the emotional impact of UC during routine appointments was less of a priority for physicians, compared with patients.ConclusionsThe data from this global survey highlight that patients with UC experience diagnostic delay, poor disease control, and adverse impact on their quality of life. Patients report UC to be a mentally exhausting condition; however, emotional and mental health issues are infrequently discussed at routine appointments.
| S-EPMC8528151 | biostudies-literature