Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

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

OBJECTIVE: Vedolizumab is a gut-selective antibody to α4ß7 integrin for the treatment of ulcerative colitis (UC) and Crohn's 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.

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 α4ß7 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 ≤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 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.).

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

BACKGROUND & AIMS: 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 α4ß7, as induction therapy. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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: NCT01224171.

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.

OBJECTIVES: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients. MATERIALS AND METHODS: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design. RESULTS: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37). CONCLUSIONS: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Program.

BACKGROUND AND AIMS: Ulcerative colitis (UC), a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency (SF), rectal bleeding (RB), bowel urgency (BU), abdominal pain (AP), and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, "comprehensive symptom control", defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at week 4. METHODS: The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo (PBO) and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis. RESULTS: By Week (W)2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52. CONCLUSIONS: Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks. [NCT03518086; NCT03524092].

Efficacy and safety of mirikizumab as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a subgroup analysis of the global phase 3 LUCENT-1 and LUCENT-2 studies.

BACKGROUND/AIMS: Mirikizumab is a p19-directed anti-interleukin-23 antibody with potential efficacy against ulcerative colitis (UC). We evaluated the efficacy and safety of mirikizumab in a Japanese subpopulation with moderately to severely active UC from the LUCENT-1 and LUCENT-2 studies. METHODS: LUCENT-1 and LUCENT-2 were phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab therapy in adults with moderately to severely active UC. LUCENT-1 was a 12-week induction trial where patients were randomized 3:1 to receive intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W). Patients achieving a clinical response with mirikizumab following the induction study were re-randomized 2:1 to double-blind treatment with either mirikizumab 200 mg or placebo subcutaneously Q4W during the 40-week maintenance study. The primary outcomes were clinical remission at week 12 of LUCENT-1 and week 40 of LUCENT-2. RESULTS: A total of 137 patients enrolled in Japan were randomized to mirikizumab (n = 102) or placebo (n = 35). Compared with placebo, patients who received mirikizumab showed numerically higher clinical remission at week 12 of induction (32.4% [n = 33] vs. 2.9% [n = 1]) and at week 40 of maintenance (48.9% [n = 23] vs. 28.0% [n = 7]). A greater number of patients achieved key secondary endpoints in the mirikizumab group compared with placebo. The frequency of treatment-emergent adverse events was similar across mirikizumab and placebo groups. Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Mirikizumab induction and maintenance treatments were effective in Japanese patients with moderately to severely active UC. No new safety concerns were identified.

Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52.

INTRODUCTION: Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo. METHODS: In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified. RESULTS: Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52. DISCUSSION: Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.

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 α4ß7 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.

A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab.

Vedolizumab is a humanized anti-α4ß7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4ß7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t ½ ß) was estimated to be 25.5 days; linear clearance (CLL) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL. Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL. A positive exposure-efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure-efficacy relationships, and immunogenicity of vedolizumab.

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.

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.

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

OBJECTIVE: This 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. METHODS: Following 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. RESULTS: Twenty-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%). CONCLUSIONS: Systemic 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 IDENTIFIER: NCT00962091.

Vedolizumab, a monoclonal antibody to the gut homing α4ß7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype.

Vedolizumab, a gut-homing α4ß7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohn's disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an α4ß7 and α4ß1 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.

Smoking cessation in primary care: a clinical effectiveness trial of two simple interventions.

BACKGROUND: Many primary care practices do not have systematic protocols to identify patients who smoke or to encourage clinicians to provide smoking cessation advice. We designed a study to assess the relative effectiveness of two brief interventions on screening for smoking, physician cessation advice and patient smoking cessation rates. METHODS: We performed a nonrandomized comparison of alternative strategies for smoking cessation at a hospital-based adult primary care practice. Each intervention was implemented on a separate practice team. The "minimal" intervention consisted of a smoking status "vital sign" stamp which documented patient smoking status. The "enhanced" intervention consisted of a five-question form that assessed patient level of cessation readiness and provided cessation-counseling prompts for clinicians. Medical record documentation of screening for smoking and cessation advice and self-reported patient smoking cessation rates were collected 8-10 months after implementation. RESULTS: Smoking status was documented at 86%, 91%, and 49%, and cessation advice at 38%, 47%, and 30% of visits on the minimal, enhanced, and control teams, respectively (P < 0.001 for smoking status and P = 0.014 for advice). Self-reported patient smoking cessation was higher on the enhanced team (12%) compared with the minimal (2%) and control (4%) teams (P < 0.001). CONCLUSIONS: A short questionnaire that assesses readiness-to-quit and provides documentation of cessation advice improves rates of clinician cessation advice and patient smoking cessation compared with no intervention.