Catherine Milch

Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Vedolizumab as induction and maintenance therapy for Crohn's disease

BACKGROUND The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohns disease is unknown. METHODS In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohns disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohns Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS Vedolizumab-treated patients with active Crohns disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

The safety of vedolizumab for ulcerative colitis and Crohn's disease

Objective Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohns disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Conclusions Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. Trial registration number NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Voluntary Electronic Reporting of Medical Errors and Adverse Events

OBJECTIVE: To describe the rate and types of events reported in acute care hospitals using an electronic error reporting system (e-ERS).DESIGN: Descriptive study of reported events using the same e-ERS between January 1, 2001 and September 30, 2003.SETTING: Twenty-six acute care nonfederal hospitals throughout the U.S. that voluntarily implemented a web-based e-ERS for at least 3 months.PARTICIPANTS: Hospital employees and staff.INTERVENTION: A secure, standardized, commercially available web-based reporting system.RESULTS: Median duration of e-ERS use was 21 months (range 3 to 33 months). A total of 92,547 reports were obtained during 2,547,154 patient-days. Reporting rates varied widely across hospitals (9 to 95 reports per 1,000 inpatient-days; median =35). Registered nurses provided nearly half of the reports; physicians contributed less than 2%. Thirty-four percent of reports were classified as nonmedication-related clinical events, 33% as medication/infusion related, 13% were falls, 13% as administrative, and 6% other. Among 80% of reports that identified level of impact, 53% were events that reached a patient (“patient events”), 13% were near misses that did not reach the patient, and 14% were hospital environment problems. Among 49,341 patient events, 67% caused no harm, 32% temporary harm, 0.8% life threatening or permanent harm, and 0.4% contributed to patient deaths.CONCLUSIONS: An e-ERS provides an accessible venue for reporting medical errors, adverse events, and near misses. The wide variation in reporting rates among hospitals, and very low reporting rates by physicians, requires investigation.

Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype

Vedolizumab, a gut-homing α4β7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohns disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an α4β7 and α4β1 integrin antagonist), has raised concern that vedolizumab may convey a similar risk. Natalizumab is believed to impair central nervous system immune surveillance by affecting cerebrospinal fluid (CSF) lymphocyte counts and the CD4:CD8 ratio. To determine if vedolizumab elicits similar effects, we examined CSF of healthy volunteers by flow cytometry for T-lymphocyte surface markers 5 weeks after administration of intravenous vedolizumab 450 mg. No significant changes were observed in CSF T-lymphocyte populations.

Efficacy of Vedolizumab in Ulcerative Colitis by Prior Treatment Failure in GEM-INI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial: P-28

BACKGROUND: We assessed the effect of vedolizumab (VDZ), an investigational, gut-selective monoclonal antibody targeting a4b7 integrin, over 52 wks of therapy in patients with moderately to severely active ulcerative colitis in whom at least 1 prior therapy had failed. METHODS: Eligible adult patients had a Mayo score 6 and endoscopic subscore 2 despite corticosteroids (CSs), purine antimetabolites, and/or TNFa antagonists. After 2 induction doses of VDZ (wk 0, wk 2), patients with clinical response (reduction in Mayo score of 3 points and 30% from baseline, plus decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore 1 point) to VDZ at wk 6 were randomized 1:1:1 to VDZ 300 mg IV q4wks, VDZ 300 mg IV q8wks, or placebo (PBO) for 46 wks. Clinical remission was defined as complete Mayo score (CMS) or partial Mayo score (PMS) 2 and no individual subscore >1; clinical response was based on PMS, as a reduction 2 points and 25% from baseline; durable mucosal healing, as Mayo endoscopic subscore 1 at both wks 6 and 52. Because the defined study endpoints used both CMS and PMS, analyses were conducted to evaluate agreement; moderate to substantial agreement was found between clinical response and remission endpoints as defined by CMS and PMS at wks 6 and 52. RESULTS: Among patients with a clinical response to VDZ at wk 6 (intention-totreat [ITT] population, N 1⁄4 373), decreases in PMS occurred as early as wk 2 (Fig 1). After successful induction, PMS remained substantially lower than baseline in both VDZ groups through wk 52, whereas an increase in PMS was noted starting at wk 22 in the PBO group. Mean vedolizumab trough concentrations in the placebo group declined over time and were below quantitation limits at wk 22. In the ITT population, remission rates by PMS in the VDZ groups remained stable, whereas PBO remission rates decreased, over the course of the maintenance phase (Fig 2). Durable mucosal healing was achieved by 42.6%, 43.2%, and 17.5% of patients in the VDZ q8wks, VDZ q4wks, and PBO groups, respectively (P < 0.0001 for both comparisons of VDZ vs PBO). Median CS dose declined over the maintenance phase in both VDZ groups, compared with rising CS use after wk 26 in the PBO group (Fig 3). In patients blinded to treatment who did not achieve a clinical response by wk 6 (n 1⁄4 174), 25.0% of VDZ vs 14.6% of PBO patients achieved clinical response, and 8.7% vs 4.9% clinical remission, as determined by PMS by wk 10. CONCLUSION(S): In patients who responded to VDZ by wk 6, treatment effect was observed as early as wk 2; sustained reductions in PMS were observed in VDZ-treated patients over a 1-year period. Clinical remission rates in VDZ patients remained stable during the maintenance phase. Durable mucosal healing was achieved in more than twice as many VDZ patients as PBO patients. Continued dosing with VDZ induced response and remission among patients who did not achieve response at wk 6.

Emerging Safety Profile of Vedolizumab: A novel, selective Integrin Inhibitor for the treatment of IBD: P-0025.

then every 8 wks for one year. The study endpoint was 1 yr endoscopic recurrence. To evaluate whether infliximab increased immediate post-operative complications, we analyzed those AEs that occurred within 8 wks of surgery. RESULTS: 24 pts were randomized to infliximab (11 pts) or placebo (13 pts) after intestinal resection for CD. The mean time to first postop infusion was 20 days (range 14 – 25 days). Over the course of 1 yr, there were 20 total AEs, but no difference between infliximab and placebo pts; 11 vs. 9, respectively, p 0.10. Within 8 wks of surgery, the number of AEs was also similar between the two groups; 3 infliximab and 5 placebo pts, p 0.68. The 3 infliximab related AEs were viral upper respiratory infection, infusion reaction, and abdominal pain. There were no complications related to wound healing or surgically related infection. CONCLUSIONS: Initiation of infliximab within 4 wks of intestinal resection for CD appears to be safe. CD pts treated with infliximab did not have problems with wound healing or other surgically related complications.

Sustained Therapeutic Benefit of Vedolizumab Throughout 1 Year in Ulcerative Colitis in GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial: P-27

BACKGROUND: We assessed the effect of vedolizumab (VDZ), an investigational, gut-selective monoclonal antibody targeting a4b7 integrin, over 52 wks of therapy in patients with moderately to severely active ulcerative colitis in whom at least 1 prior therapy had failed. METHODS: Eligible adult patients had a Mayo score 6 and endoscopic subscore 2 despite corticosteroids (CSs), purine antimetabolites, and/or TNFa antagonists. After 2 induction doses of VDZ (wk 0, wk 2), patients with clinical response (reduction in Mayo score of 3 points and 30% from baseline, plus decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore 1 point) to VDZ at wk 6 were randomized 1:1:1 to VDZ 300 mg IV q4wks, VDZ 300 mg IV q8wks, or placebo (PBO) for 46 wks. Clinical remission was defined as complete Mayo score (CMS) or partial Mayo score (PMS) 2 and no individual subscore >1; clinical response was based on PMS, as a reduction 2 points and 25% from baseline; durable mucosal healing, as Mayo endoscopic subscore 1 at both wks 6 and 52. Because the defined study endpoints used both CMS and PMS, analyses were conducted to evaluate agreement; moderate to substantial agreement was found between clinical response and remission endpoints as defined by CMS and PMS at wks 6 and 52. RESULTS: Among patients with a clinical response to VDZ at wk 6 (intention-totreat [ITT] population, N 1⁄4 373), decreases in PMS occurred as early as wk 2 (Fig 1). After successful induction, PMS remained substantially lower than baseline in both VDZ groups through wk 52, whereas an increase in PMS was noted starting at wk 22 in the PBO group. Mean vedolizumab trough concentrations in the placebo group declined over time and were below quantitation limits at wk 22. In the ITT population, remission rates by PMS in the VDZ groups remained stable, whereas PBO remission rates decreased, over the course of the maintenance phase (Fig 2). Durable mucosal healing was achieved by 42.6%, 43.2%, and 17.5% of patients in the VDZ q8wks, VDZ q4wks, and PBO groups, respectively (P<0.0001 for both comparisons of VDZ vs PBO). Median CS dose declined over the maintenance phase in both VDZ groups, compared with rising CS use after wk 26 in the PBO group (Fig 3). In patients blinded to treatment who did not achieve a clinical response by wk 6 (n 1⁄4 174), 25.0% of VDZ vs 14.6% of PBO patients achieved clinical response, and 8.7% vs 4.9% clinical remission, as determined by PMS by wk 10. CONCLUSION(S): In patients who responded to VDZ by wk 6, treatment effect was observed as early as wk 2; sustained reductions in PMS were observed in VDZ-treated patients over a 1-year period. Clinical remission rates in VDZ patients remained stable during the maintenance phase. Durable mucosal healing was achieved in more than twice as many VDZ patients as PBO patients. Continued dosing with VDZ induced response and remission among patients who did not achieve response at wk 6.

Differences in triage thresholds for patients presenting with possible acute coronary syndromes: More than meets the eye.

Background Many studies have shown differences in cardiac care by racial/ethnic groups without accounting for institutional factors at the location of care. Objective Exploratory analysis of the effect of hospital funding status (public vs private) on emergency department (ED) triage decision making for patients with symptoms suggestive of acute coronary syndromes (ACSs) and on the likelihood of ED discharge for patients with confirmed ACS. Study Design and Setting Secondary analysis of data from a randomized controlled trial of 10,659 ED patients with possible ACS in five urban academic public and five private hospitals. The main outcome measures were the sensitivity and specificity of hospital admission for the presence of ACS at public and private hospitals and the adjusted odds of a patient with ACS not being hospitalized at public versus private hospitals. Results Of 10,659 ED patients, 1,856 had confirmed ACS. For patients with suspected ACS, triage decisions at private hospitals were considerably more sensitive (99 vs 96%; p < .001) but less specific (30 vs 48%; p < .001) than at public hospitals. The difference between hospital types persisted after adjustment for multiple patient-level and hospital-level characteristics. Conclusion Significant differences in triage for patients with suspected ACS exist between public and private hospital EDs, even after adjustment for multiple patient demographic, clinical, and institutional factors. Further studies are needed to clarify the causes of the differences.

Vedolizumab Induction Therapy for Patients With Crohn’s Disease and Prior Anti-TNF Antagonist Failure: A Randomized, Placebo-controlled, Double-blind, Multicenter Trial: P-26

agent has not been thoroughly evaluated. A post hoc analysis evaluated this question in a 26-week randomized, double-blind, placebo-controlled trial performed in adults with moderate to severe Crohn’s disease who were stratified by corticosteroid use at baseline (PRECiSE 2 trial, NCT00152425). METHODS: Adult patients (N 1⁄4 668) with active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] 220–450) were enrolled and received open-label induction therapy with certolizumab pegol (400 mg administered subcutaneously at Weeks 0, 2, and 4). Patients who responded at Week 6 to certolizumab pegol induction therapy (the intent-to-treat [ITT] population) were randomized to continuous therapy with 400 mg certolizumab pegol or placebo every 4 weeks through Week 24, with follow-up at Week 26. While corticosteroid tapering was not mandatory, the number of patients eligible to taper corticosteroids was evaluated, along with the number of patients that initiated corticosteroid tapering between Weeks 8 and 12. Patients who, in the investigator’s opinion, showed a clinical response 8-12 weeks from their first injection of certolizumab pegol were eligible to taper corticosteroids. The decision to initiate corticosteroid tapering was at the discretion of the investigator. Corticosteroid-free clinical remission (defined as a CDAI score of 150 and discontinuation of all oral steroids) was evaluated in the certolizumab pegol arm at Week 26 using a last observation carried forward imputation. RESULTS: Among 215 patients with a response to certolizumab pegol induction therapy at Week 6 (the ITT population in the certolizumab pegol arm), 34% (74/ 215) were treated with corticosteroids at baseline. 70% (52/74) of the patients in the certolizumab pegol arm on corticosteroids at baseline were eligible to taper corticosteroid treatment. Of these eligible patients, 87% (45/52) initiated a taper of their corticosteroid treatment. 31% (14/45) of the population on corticosteroids at baseline that initiated a taper were in a corticosteroid-free clinical remission at Week 26. Additionally, 38% (82/215) of the ITT population and 49% (68/ 140) of the population not on corticosteroids at baseline were in corticosteroidfree clinical remission at Week 26. CONCLUSION(S): Approximately one third of patients on corticosteroids at baseline were able to achieve clinical remission and successfully taper corticosteroids with certolizumab pegol in the PRECiSE 2 trial. Further investigation is warranted regarding the significant proportion of patients who were able to taper off of corticosteroids while on maintenance therapy with certolizumab pegol, as well as the reasons that some patients did not initiate a corticosteroid taper when they were eligible.