Immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine (ERVEBO®) in African clinical trial participants by age, sex, and baseline GP-ELISA titer: A post hoc analysis of three Phase 2/3 trials.

BACKGROUND: ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was advanced through clinical development by Merck & Co., Inc., Rahway, NJ, USA in collaboration with multiple partners to prevent Ebola virus disease (EVD) and has been approved for human use in several countries. METHODS: We evaluated data from three Phase 2/3 clinical trials conducted in Liberia (PREVAIL), Guinea (FLW), and Sierra Leone (STRIVE) during the 2013-2016 West African EVD outbreak to assess immune responses using validated assays. We performed a post hoc analysis of the association of vaccine response with sex, age (18-50 yrs & >50 yrs), and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (<200 & ≥200 EU/mL), including individual study (PREVAIL, FLW, or STRIVE) data and pooled data from all 3 studies. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 28, 180, and 365 postvaccination. RESULTS: In the overall pooled population, in all subgroups, and in each trial independently, GP-ELISA and PRNT geometric mean titers increased from BL, generally peaking at Day 28 and persisting through Day 365. Immune responses were greater in women and participants with BL GP-ELISA ≥ 200 EU/mL, but did not differ across age groups. CONCLUSION: These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response through 12 months postvaccination in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in women and participants with pre-existing immunity are consistent with those described previously and for other vaccines. Trials were registered as follows: PREVAIL: ClinicalTrials.gov NCT02344407; FLW: Pan African Clinical Trials Registry PACTR201503001057193; STRIVE: ClinicalTrials.gov NCT02378753. Protocols V920-009, 011, and 018.

Development of Pandemic Vaccines: ERVEBO Case Study.

Preventative vaccines are considered one of the most cost-effective and efficient means to contain outbreaks and prevent pandemics. However, the requirements to gain licensure and manufacture a vaccine for human use are complex, costly, and time-consuming. The 2013-2016 Ebola virus disease (EVD) outbreak was the largest EVD outbreak to date and the third Public Health Emergency of International Concern in history, so to prevent a pandemic, numerous partners from the public and private sectors combined efforts and resources to develop an investigational Zaire ebolavirus (EBOV) vaccine candidate (rVSVΔG-ZEBOV-GP) as quickly as possible. The rVSVΔG-ZEBOV-GP vaccine was approved as ERVEBOTM by the European Medicines Authority (EMA) and the United States Food and Drug Administration (FDA) in December 2019 after five years of development. This review describes the development program of this EBOV vaccine, summarizes what is known about safety, immunogenicity, and efficacy, describes ongoing work in the program, and highlights learnings applicable to the development of pandemic vaccines.

Corrigendum to: Renal Impairment, C. difficile Recurrence, and the Differential Effect of Bezlotoxumab: A Post Hoc Analysis of Pooled Data From 2 Randomized Clinical Trials.

[This corrects the article DOI: 10.1093/ofid/ofaa248.].

Estimation of the correlates of protection of the rVSVΔG-ZEBOV-GP Zaire ebolavirus vaccine: a post-hoc analysis of data from phase 2/3 clinical trials.

BACKGROUND: Establishment of immune correlates of protection can provide a measurable criterion for assessing protection against infection or disease. For some vaccines, such as the measles vaccine, antibodies serve as the correlate of protection, but for others, such as human papillomavirus, the correlate of protection remains unknown. Merck & Co, Kenilworth, NJ, USA, in collaboration with multiple partners, developed a live recombinant vesicular stomatitis virus vaccine (rVSVΔG-ZEBOV-GP [ERVEBO]) containing the Zaire ebolavirus glycoprotein (GP) in place of the recombinant vesicular stomatitis virus GP to prevent Ebola virus disease. Seroresponse, defined as post-vaccination GP-ELISA of 200 ELISA units (EU) per mL or higher and two-times or more above baseline, was proposed; however, correlates of protection have not been determined. The objective of this post-hoc analysis was to infer possible correlates of protection for rVSVΔG-ZEBOV-GP. METHODS: In this post-hoc analysis we included vaccinated participants with serology data from three phase 2/3 immunogenicity trials in Guinea, Sierra Leone, and Liberia (n=2199). Two of the trials were open-label, single-arm trials (one randomised [STRIVE], one non-randomised [FLW]); and one trial was randomised, placebo-controlled with two vaccine comparators (PREVAIL). Endpoints were total IgG antibody response (EU per mL) to rVSVΔG-ZEBOV-GP measured by GP-ELISA and neutralising antibody response to rVSVΔG-ZEBOV-GP measured by plaque reduction neutralisation test at days 14, 28, 180, and 365 after vaccination. Reverse cumulative distribution curves of the antibody concentrations were used to estimate statistical correlates of protection between 70% and 100% that might be applied to vaccine efficacy and effectiveness estimates. FINDINGS: Although GP-ELISA and plaque reduction neutralisation tests showed similar response patterns, GP-ELISA provided a wider range of measurable titres and better differentiation for estimating correlates of protection compared with the plaque reduction neutralisation test. At day 14 after vaccination in the FLW trial, 1060 (100%) of 1060 participants had GP-ELISA levels at or above 68 EU per mL and 742 (70%) of 1060 had levels at or above 313 EU per mL. At day 28 after vaccination in the pooled population, 1953 (100%) of 1953 participants had levels at or above 73 EU per mL and 1368 (70%) of 1953 participants had levels at or above 735 EU per mL. GP-ELISA seroresponse 200 EU per mL or higher and two-times or more increase in antibody level from baseline occurred in 80% or higher of participants at each assessment and in 94% or higher of participants at any time after vaccination. INTERPRETATION: Our results are consistent with previous work suggesting that seroresponse defined as GP-ELISA of 200 EU per mL or higher and two-times or more from baseline associated with vaccination might be the most appropriate dichotomous correlate of protection and falls within the seroprotective threshold range described herein. FUNDING: Merck Sharp & Dohme, Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services.

Renal Impairment, C. difficile Recurrence, and the Differential Effect of Bezlotoxumab: A Post Hoc Analysis of Pooled Data From 2 Randomized Clinical Trials.

BACKGROUND: Renal impairment is not a consistently cited risk factor for recurrent Clostridioides difficile infection (rCDI). We examined the association between renal impairment and rCDI and the effect of bezlotoxumab, an anti-toxin B monoclonal antibody, in reducing rCDI in participants with renal impairment. METHODS: We pooled data from 2 randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials conducted in participants receiving bezlotoxumab or placebo infusion during oral antibacterial drug treatment for CDI. We assessed the association between renal impairment and rCDI in placebo-treated participants and evaluated the effect of bezlotoxumab vs placebo in reducing rCDI among participants with renal impairment, defined as an estimated glomerular filtration rate <90 mL/min. RESULTS: The proportion of placebo-treated participants experiencing rCDI within 12 weeks was higher in those with renal impairment (n = 919) vs those without renal impairment (n = 612; 36.6% and 27.7%, respectively; difference, 8.9%; 95% CI, 1.3% to 16.3%). Renal impairment was significantly associated with a higher rate of recurrence in placebo-treated participants lacking commonly recognized risk factors for rCDI (renal impairment as only risk factor, 28.8%; vs normal renal function and no risk factors, 12.5%; difference, 16.3%; 95% CI, 3.4% to 28.8%). Among all participants with renal impairment, the rate of rCDI was 19.5% among bezlotoxumab-treated vs 36.6% among placebo-treated participants (difference, -17.1%; 95% CI, -23.4% to -10.6%). CONCLUSIONS: This post hoc analysis adds to the literature suggesting an association of renal impairment as an independent risk factor for rCDI and provides preliminary evidence that patients with renal impairment who suffer with CDI may benefit from adjunctive treatment with bezlotoxumab.

Analysis of C. difficile infection-related outcomes in European participants in the bezlotoxumab MODIFY I and II trials.

The MODIFY I/II trials demonstrated that bezlotoxumab, a human monoclonal antibody against Clostridioides difficile toxin B, given during antibiotic treatment for Clostridioides difficile infection (CDI) significantly reduced C. difficile recurrence (rCDI) in adults at high risk for rCDI. Efficacy of CDI-directed intervention may depend on ribotype regional epidemiology, and patient characteristics. This post hoc analysis assessed the efficacy of bezlotoxumab in the subgroup of MODIFY I/II trial participants enrolled in Europe. Data from the bezlotoxumab (10 mg/kg single intravenous infusion) and placebo (0.9% saline) groups from MODIFY I/II were compared to assess initial clinical cure (ICC), rCDI, all-cause, and CDI-associated rehospitalizations within 30 days of discharge, and mortality through 12 weeks post-infusion. Of 1554 worldwide participants, 606 were from Europe (bezlotoxumab n = 313, 51%; placebo n = 292; 48%). Baseline characteristics were generally similar across groups, although there were more immunocompromised participants in the bezlotoxumab group (27.2%) compared with placebo (20.1%). Fifty-five percent of participants were female, and 86% were hospitalized at randomization. The rate of ICC was similar between treatment groups. The rate of rCDI in the bezlotoxumab group was lower compared with placebo among European participants overall, and among those with ≥ 1 risk factor for rCDI. Bezlotoxumab reduced 30-day CDI-associated rehospitalizations compared with placebo. These results are consistent with overall results from the MODIFY trials and demonstrate that bezlotoxumab reduces rCDI and CDI-associated rehospitalizations in European patients with CDI. MODIFY I/II (NCT01241552 and NCT01513239).

Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials.

BACKGROUND: Patients with recurrent Clostridium difficile infection (rCDI) are more likely to have a hospital readmission and spend increased time in inpatient settings compared with patients with primary CDI. MODIFY I and II demonstrated that bezlotoxumab significantly reduced rCDI vs placebo. A post hoc within-trial analysis assessed whether bezlotoxumab was associated with a reduction in cumulative inpatient-days. METHODS: Data were pooled from the MODIFY trials to estimate the cumulative hospitalized days summed over the 84-day follow-up period. We adjusted inpatient use data from pooled MODIFY I and II for survival and censoring to estimate 84-day cumulative inpatient-days, overall and for subgroups. Treatment effects were obtained using recycled predictions based on trial protocol and rCDI risk, and 95% confidence intervals were obtained using 1000 bootstrap replicates. RESULTS: Mean cumulative inpatient-days were greater in the placebo arm (14.1 days) vs the bezlotoxumab arm (12.1 days) in the overall population. The mean difference between treatment groups was 2.1 days (95% confidence interval, -0.4 to -3.7). This was consistent in participants with risk factors for rCDI: age ≥65 years, compromised immunity, severe CDI, prior CDI, and ribotype 027/078/244 infection. As the number of risk factors increased, bezlotoxumab resulted in greater reductions in the number of inpatient-days compared with placebo (difference: -1.2 days, -2.3 days, -2.5 days, and -3.0 days for 0, 1, 2, and ≥3 risk factors, respectively). CONCLUSIONS: Bezlotoxumab was associated with a reduction in cumulative inpatient-days, suggesting that treatment with bezlotoxumab may substantially reduce rCDI-associated health care resource use. Trial registrations. MODIFY I (MK-3415A-001, NCT01241552) and II (MK-3415A-002, NCT01513239).

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence.

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results: The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions: The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Antiplatelet Therapy and Clinical Outcomes Following Myocardial Infarction Among Patients in a U.S. Employer-Based Insurance Database.

BACKGROUND: Estimates of residual cardiovascular risks among patients who have experienced a recent acute myocardial infarction (MI) are predominantly derived from secondary prevention trial populations, patient registries, and population-based cohorts. OBJECTIVE: To generate real-world evidence of antiplatelet treatment and recurrent events following MI in patients on antiplatelet treatment among commercial, employer-based insured patients in a large administrative database. METHODS: This was a retrospective cohort claims database study using the Truven Health MarketScan Commercial Claims and Encounters and Medicare Supplemental databases between 2007-2011. Patients with an acute MI hospitalization with a discharge date between 2008 and 2010 were included. Excluded were those patients with documentation of stroke, transient ischemic attack (TIA), or severe bleeding at or before index hospitalization and with concomitant use of anticoagulant therapy following index hospitalization. Patients treated with clopidogrel following the index MI hospitalization were followed up to 1 year for repeat MI, stroke, and coronary revascularization. RESULTS: Among 33,943 post-MI continuous clopidogrel users without history of stroke, TIA, or bleeding, 22% had diabetes, whereas angina and renal impairment were less prevalent (5% and 7%, respectively). Over the 1-year follow-up, 2.4% experienced a repeat MI or stroke, and 8.2% underwent coronary revascularization. Angina, diabetes, and renal impairment were associated with elevated 1-year risk of repeat MI or stroke. CONCLUSIONS: This study suggests that there is residual cardiovascular risk, although relatively low, in an insured, secondary prevention population on antiplatelet treatment following an MI. In patients with MI, identifying angina, diabetes, and renal impairment may aid risk stratification and guide the effective management of these higher-risk patients. DISCLOSURES: Funding for this research was provided by Merck & Co. Although Merck & Co. formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the company. Reed Chase, Wu, Mavros, Heithoff, and Hanson are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co., and may own stock and/or hold stock options in the company. Patel was an employee of Merck & Co. during the conduct of this study and preparation of the manuscript. Simpson is a paid consultant for Merck, Pfizer, and Amgen and has received speaker's fees from Merck and Pfizer. Study concept and design were contributed by all authors except Hanson. Heifhoff and Patel collected the data, and data interpretation was performed by Simpson, Mavros, Patel, Wu, and Hanson. The manuscript was written by Hanson, Mavros, and Patel and revised by Heithoff, Wu, Simpson, and Reed Chase.

Geographic variation and risk factors for systemic and limb ischemic events in patients with symptomatic peripheral artery disease: Insights from the REACH Registry.

BACKGROUND: Patients with symptomatic peripheral artery disease (PAD) are at high risk of ischemic events. However, data about predictors of this risk are limited. HYPOTHESIS: We analyzed baseline characteristics and 4-year follow-up of patients enrolled in the international REduction of Atherothrombosis for Continued Health (REACH) Registry with symptomatic PAD and no history of stroke/transient ischemic attack to describe annual rates of recurrent ischemic events globally and geographically. METHODS: The primary outcome was systemic ischemic events (composite of cardiovascular death, myocardial infarction, or stroke) at 4 years. The secondary outcome was limb ischemic events (composite of lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD) at 2 years. Multivariate analysis identified risk factors associated with recurrent ischemic events. RESULTS: The primary endpoint rate reached 4.7% during the first year and increased continuously (by 4%-5% each year) to 17.6% by year 4, driven mainly by cardiovascular mortality (11.1% at year 4). Japan experienced lower adjusted ischemic rates (P < 0.01) vs North America. Renal impairment (P < 0.01), congestive heart failure (P < 0.01), history of diabetes (P < 0.01), history of myocardial infarction (P = 0.01), vascular disease (single or poly, P < 0.01), and older age (P < 0.01) were associated with increased risk of systemic ischemic events, whereas statin use was associated with lower risk (P = 0.03). The limb ischemic event rate was 5.7% at 2 years. CONCLUSIONS: Four-year systemic ischemic risk in patients with PAD and no history of stroke or transient ischemic attack remains high, and was mainly driven by cardiovascular mortality.

Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection.

Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Randomized trial assessing the safety and efficacy of sitagliptin in Chinese patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or combined with metformin.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant burden in China, where approximately 114 million patients have been diagnosed with diabetes. Chinese patients present with prominent ß-cell failure, with resulting deficiency in insulin secretion, particularly early phase insulin secretion leading to postprandial hyperglycemia. Sitagliptin, a selective once-daily oral dipeptidyl peptidase-4 inhibitor, has been shown to improve glycemic control as monotherapy and in combination with other antihyperglycemic agents, including sulfonylureas and metformin. METHODS: This was a multicenter randomized double-blind placebo-controlled study conducted in China. The study assessed the safety and efficacy of the addition of sitagliptin 100 mg once daily versus placebo on changes from baseline at Week 24 in HbA1c, fasting plasma glucose (FPG) and 2-h post-meal glucose (PMG). Patients were aged 18-79 years, had T2DM with inadequate glycemic control, and were taking a sulfonylurea, with or without metformin. RESULTS: After 24 weeks, sitagliptin reduced HbA1c, FPG, and 2-h PMG significantly more than placebo (between-treatment differences: -0.61 %, -16.8 mg/dL, and -32.9 mg/dL, respectively; P < 0.001 for all). The addition of sitagliptin was generally well tolerated, with a comparable incidence of adverse events and drug-related adverse events in both treatment groups. The sitagliptin group had a higher incidence of symptomatic hypoglycemia than the placebo group (25/248 [10.1 %] vs 13/249 [5.2 %], respectively; P = 0.042). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycemic control in Chinese patients with T2DM who had inadequate glycemic control with sulfonylurea, with or without metformin therapy. The addition of sitagliptin was generally well tolerated. (clinicaltrials.gov: NCT01590771).

Effect on Fasting Serum Glucose Levels of Adding Ezetimibe to Statins in Patients With Nondiabetic Hypercholesterolemia.

Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7 mg/dl with ezetimibe/statin; 0.2 to 4.6 mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4 mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG ≥126 mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy.

Residual Ischemic Risk and Its Determinants in Patients With Previous Myocardial Infarction and Without Prior Stroke or TIA: Insights From the REACH Registry.

BACKGROUND: Although the rate of in-hospital ischemic events after myocardial infarction (MI) has dramatically decreased, long-term residual risk may remain substantial. However, most of the information on current residual risk is derived from highly selected randomized trials. HYPOTHESIS: In patients with previous MI and no prior ischemic stroke/transient ischemic attack (TIA), residual ischemic risk increases over time. METHODS: Using the international Reduction of Atherothrombosis for Continued Health (REACH) registry, we analyzed baseline characteristics and 4-year follow-up of patients with previous MI and no history of stroke/TIA to describe annual rates of recurrent ischemic events globally and by geography. The primary outcome was the composite of cardiovascular death, MI, or stroke. Multivariate analysis identified risk factors associated with recurrent ischemic events. RESULTS: Data from 16 770 patients enrolled at 5587 sites in 44 countries were analyzed. The rate of the primary outcome increased annually from 4.7% during year 1 to reach a 4-year rate of 15.1%. Compared with North America, Japan experienced lower ischemic event rates (P < 0.01), whereas Eastern Europe (P < 0.01) and the Middle East (P = 0.01) experienced higher ischemic event rates. The presence of congestive heart failure, polyvascular disease, diabetes, atrial fibrillation or flutter, and older age were associated with increased residual risk (all P < 0.01). Statin use was associated with lower ischemic risk (P < 0.01). CONCLUSIONS: In this study, residual ischemic risk after MI accrued progressively up to 4 years of follow-up, emphasizing the value of intensive secondary prevention strategies to minimize residual risk.

A phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma.

This study was undertaken to evaluate safety and pharmacokinetics and to determine treatment doses of vorinostat plus bortezomib in Japanese patients with relapsed or refractory multiple myeloma (MM). Of 9 originally enrolled patients, 2 were refractory to bortezomib, and both experienced dose-limiting toxicity (DLT), prompting a protocol amendment to exclude bortezomib-refractory individuals. Patients not considered bortezomib refractory (N = 7) received 21-day cycles of 1.3 mg/m(2) intravenous bortezomib (Days 1, 4, 8, and 11) and oral vorinostat 400 mg (Days 1 through 14) and were further evaluated. Vorinostat and bortezomib treatment doses were determined by DLT and safety, tolerability, and treatment response were assessed. Of 7 enrolled patients, 6 were evaluated, and one developed DLTs. The most common adverse events were leukopenia, neutropenia, thrombocytopenia, diarrhea, nausea, decreased appetite, and vomiting. Combination of vorinostat plus bortezomib did not increase vorinostat exposure at Day 11 [AUC0-24 h ratio (95% CI) = 1.08 (0.80, 1.45)]; geometric mean AUC0-24 h ratio for bortezomib (90% CI) was 1.96 (1.24-3.12). Objective therapeutic response occurred in 3 patients, including 1 complete response and 2 partial responses. Vorinostat 400 mg plus bortezomib 1.3 mg/m(2) was safe and well-tolerated in Japanese patients with relapsed or refractory MM not considered bortezomib refractory (NCT00858234).

A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia.

BACKGROUND: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL-C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c. RESULTS: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups. CONCLUSIONS: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01611883 .

Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients.

OBJECTIVE: We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins versus statins in hypercholesterolemic patients. METHODS: An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line (statin-naïve/wash-out) or second-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6-24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were compared. RESULTS: In first-line and second-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated patients, ±covariates. Differences were small but statistically significant due to the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types, being more pronounced in second-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent trend for either therapy. CONCLUSION: In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe + statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins + ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions.

Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone.

PURPOSE: To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone. METHODS: This was an open-label, two-period, two-treatment, fixed-sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once-daily on Days 2-7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N-desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study. RESULTS: Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N-desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0-24 h (GMR 103; 90% CI 98, 108) were within the 80-125% bioequivalence criteria. The metabolite-to-parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated. CONCLUSION: Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.

Evaluation of blood pressure reduction response and responder characteristics to fixed-dose combination treatment of amlodipine and losartan: a post hoc analysis of pooled clinical trials.

Data from four clinical trials compared reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) among patients treated with amlodipine/losartan 5/50 mg vs 5/100 mg and amlodipine/losartan 5/50 mg vs amlodipine 5 mg and 10 mg. Response rate was assessed as reduction in SBP or DBP (>20/10 mm Hg) and proportion of patients achieving SBP <140 mm Hg or DBP <90 mm Hg. Patients were grouped into quartiles based on baseline SBP and DBP. Mean SBP and DBP were reduced in amlodipine/losartan 5/50 mg (n=182) and amlodipine/losartan 5/100 mg (n=95) users across all baseline quartiles. Patients using amlodipine/losartan 5/50 mg had significantly greater SBP and DBP reductions vs amlodipine 5 mg (P=.001 and P=.02, respectively). Amlodipine/losartan 5/50 mg users had significantly greater SBP reduction vs amlodipine 10 mg (SBP P=.02; DBP P=not significant). The odds of responding to therapy were significantly greater with amlodipine/losartan 5/50 mg vs amlodipine 5 mg (odds ratio, 5.33; 95% confidence interval, 1.42-25.5) and were similar vs amlodipine 10 mg (odds ratio, 0.67; 95% confidence interval, 0.017-9.51). These results support the use of combination therapy early in the treatment of hypertension.

Efficacy and safety of losartan 100 mg/hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension: two randomized, controlled trials.

Two randomized studies were designed to assess the safety, tolerability and efficacy of losartan 100 mg (L100) plus hydrochlorothiazide 12.5 mg (H12.5) in a single fixed-dose combination. In one study, subjects received losartan 50 mg (L50) plus H12.5 during an 8-week filter period. They were then randomized to either L100/H12.5 or L50/H12.5 for another 8 weeks, followed by L100/H12.5 for 44 weeks. The primary end point was safety of L100/H12.5 for 52 weeks. In the second study, subjects received L100 during an 8-week filter period. Subjects were then randomized to receive either L100/H12.5 or L100 for a further 8 weeks. The primary end point was change from baseline in sitting diastolic blood pressure (SiDBP) at week 8. Safety was assessed throughout both studies. L100/H12.5 reduced SiDBP and sitting systolic blood pressure (SiSBP) at 8 weeks, and when compared with L100, the differences were statistically significant for both measures (P<0.001). L100/H12.5 reductions SiDBP for 8 weeks were comparable to L50/H12.5. The efficacy of L100/H12.5 was maintained to week 52. Drug-related adverse events with an incidence ⩾ 2% in the L100/H12.5 group during the 52-week extension period were an increase in aspartate aminotransferase and in blood uric acid. Additionally, mean uric acid levels were reduced by 0.57 mg dl(-1) from baseline with long-term treatment with L100/H12.5 in subjects whose baseline uric acid level was >7.0 mg dl(-1). In conclusion, L100/H12.5 was shown to be more effective than L100 at reducing SiDBP and SiSBP and showed good tolerability in Japanese patients with essential hypertension.