A programme for risk assessment and minimisation of progressive multifocal leukoencephalopathy developed for vedolizumab clinical trials

Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs

Voluntary Electronic Reporting of Medical Errors and Adverse Events: An Analysis of 92,547 Reports from 26 Acute Care Hospitals

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

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

Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. 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. 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. Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT0079093

Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed

There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy. Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101). Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups. Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT0122417

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an alpha4beta7 integrin antibody, in Crohn's 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 Crohn's 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 Crohn's Disease Activity Index [CDAI] of /=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 Crohn's 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.)

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; P1), 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.)

Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors.

ObjectiveThis study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.MethodsFollowing overnight fasting for 10 h, a single 50 mg enteric-coated tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration.ResultsTwenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median t max was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUCinf (fed- vs. fasted-state dosing) was 0.94 [90% confidence interval (CI) 0.68-1.32]. The geometric mean C max under fed conditions was 84% of that under fasted conditions (90% CI 66-106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50%), leukopenia (38%), and thrombocytopenia (21%).ConclusionsSystemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. CLINICALTRIALS.Gov identifierNCT00962091