Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

HIGH-TOOL – a strategic assessment tool for evaluating EU transport policies

Abstract In this paper the strategic transport policy assessment instrument HIGH-TOOL is presented. The model has been developed for the European Commission, allowing policy-makers to identify the most advantageous transport policies and to strategically evaluate the impacts of transport policies on transport, environment and economy. The main innovation of this policy assessment tool lies in the integration of originally independently functioning models – i.e. passenger and freight demand, demography, and vehicle stock models, as well as economic, environmental and safety assessment models. With its traffic zones at the regional level of NUTS-2 and its aggregated view on the transport system, the instrument has a relatively lean structure avoiding runtime problems, without losing the spatial dimension. What distinguishes HIGH-TOOL from all other European transport policy assessment instruments: the model is an open source tool, it is freely available and does not require any commercial software to be run. In combination with its modular structure the HIGH-TOOL model can relatively easily be adjusted to other modelling methodologies or data. It can also comparatively easily be made responsive to “new” policies which are not in the scope of the current model version. Thus the HIGH-TOOL model lays the foundation for further innovations in the assessment of transport policies and mobility concepts

A strategic assessment tool for evaluating European Transport Policies - the High-Tool approach

Decisions on transport policy measures proposed by the European Union (EU) have long-term and important impacts on economy, environment and society. Transport policy measures can lock up capital for decades and cause manifold external effects – thus, policy measures may have a tremendous scope, especially if proposed on a European level. In order to allow European policy-makers to evaluate transport polices, a strategic assessment tool has been developed to compute economic, environmental and social impacts of transport policies

Anamnestic immune response and safety of an inactivated quadrivalent influenza vaccine in primed versus vaccine-naïve children

Background: It has not yet been demonstrated whether two doses of inactivated quadrivalent influenza vaccine (IIV4) prime a booster response in infants. We evaluated the anamnestic immune response to an IIV4 in children aged 17−48 months. Methods: Children were randomized to two doses of IIV4 or control in the primary phase III study (NCT01439360). One year later, in an open-label revaccination extension study (NCT01702454), a subset of children who received IIV4 in the primary study (primed group) received one IIV4 dose and children who received control in the primary study (unprimed) received two IIV4 doses 28 days apart. The primary objective was to evaluate hemagglutination inhibition (HI) antibody titers 7 days after first IIV4 vaccination in the per-protocol cohort (N=224 primed; N=209 unprimed). Neutralizing and anti-neuraminidase antibodies were also measured. Safety was analyzed in the total vaccinated cohort (N=241 primed; N=229 unprimed). Results: An anamnestic response was observed in primed children relative to unprimed controls, measured by age-adjusted geometric mean HI titer ratios against strains homologous (A/H1N1: 9.0; B/Victoria: 3.9) and heterologous (A/H3N2: 2.7; B/Yamagata: 6.7) to those in the primary vaccination series. The anamnestic response in primed children included increases in neutralizing antibodies (mean geometric increase: 5.0–10.6) and anti-neuraminidase antibodies (4.9–8.8). No serious adverse events related to vaccination were reported. Conclusion: In this study, 2-dose priming with IIV4 induced immune memory that was recalled with 1-dose IIV4 the following year to boost HI, anti-neuraminidase, and neutralizing antibodies, even though the IIV4 strain composition partially changed

Anamnestic immune response and safety of an inactivated quadrivalent influenza vaccine in primed versus vaccine-naïve children

Background: It has not yet been demonstrated whether two doses of inactivated quadrivalent influenza vaccine (IIV4) prime a booster response in infants. We evaluated the anamnestic immune response to an IIV4 in children aged 17−48 months. Methods: Children were randomized to two doses of IIV4 or control in the primary phase III study (NCT01439360). One year later, in an open-label revaccination extension study (NCT01702454), a subset of children who received IIV4 in the primary study (primed group) received one IIV4 dose and children who received control in the primary study (unprimed) received two IIV4 doses 28 days apart. The primary objective was to evaluate hemagglutination inhibition (HI) antibody titers 7 days after first IIV4 vaccination in the per-protocol cohort (N=224 primed; N=209 unprimed). Neutralizing and anti-neuraminidase antibodies were also measured. Safety was analyzed in the total vaccinated cohort (N=241 primed; N=229 unprimed). Results: An anamnestic response was observed in primed children relative to unprimed controls, measured by age-adjusted geometric mean HI titer ratios against strains homologous (A/H1N1: 9.0; B/Victoria: 3.9) and heterologous (A/H3N2: 2.7; B/Yamagata: 6.7) to those in the primary vaccination series. The anamnestic response in primed children included increases in neutralizing antibodies (mean geometric increase: 5.0–10.6) and anti-neuraminidase antibodies (4.9–8.8). No serious adverse events related to vaccination were reported. Conclusion: In this study, 2-dose priming with IIV4 induced immune memory that was recalled with 1-dose IIV4 the following year to boost HI, anti-neuraminidase, and neutralizing antibodies, even though the IIV4 strain composition partially changed