Safety and efficacy of self-administered inhaled loxapine (ADASUVE) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial.

INTRODUCTION: There is a need for fast-acting, non-injection antiagitation treatments that are well tolerated and can be used outside of healthcare facilities. In phase II/III trials, an inhaled formulation of loxapine (ADASUVE®), a well-established, first-generation antipsychotic agent, provided rapid control of mild to moderate agitation in the hospital setting. The present study was designed to investigate the safety and efficacy of inhaled loxapine when self-administered outside the hospital setting. METHODS AND ANALYSIS: This phase IV, multicentre, single-arm, open-label clinical trial is being conducted in five countries in Europe: Spain, Germany, Norway, Romania and Austria. The aim is to include approximately 500 patients with schizophrenia or bipolar disorder who previously received and responded well to inhaled loxapine in the hospital setting. Eligible patients will be followed up for 6 months from baseline. They will be given a 10 mg dose of inhaled loxapine to self-administer outside the hospital setting to treat an agitation episode, should one occur. Patients will also be given a short-acting beta-agonist bronchodilator for treatment of possible severe respiratory side effects. The primary endpoint is incidence of serious adverse events (AEs) and respiratory AEs of special interest related to use of inhaled loxapine outside the hospital setting. Secondary endpoints include incidence of other AEs, Clinical Global Impression-Improvement scores up to 2 hours after self-administration of inhaled loxapine, time to improvement of agitation, patient satisfaction with treatment, treatment outcomes according to agitation severity and concordance between the patient (or a family member/caregiver) and the physician in scoring of agitation severity and the decision to self-administer inhaled loxapine. ETHICS AND DISSEMINATION: The protocol received ethics committee approval in the participating countries between January and August 2016. The results of this study will be disseminated through one or more scientific papers. TRIAL REGISTRATION NUMBER: EudraCT2015-003331-36; NCT02525991; Pre-results.

Assessing the Impact of Medication Adherence on Long-Term Cardiovascular Outcomes.

BACKGROUND: Although guideline-recommended therapies reduce major adverse cardiovascular events (MACE) in patients after myocardial infarction (MI) or those with atherosclerotic disease (ATH), adherence is poor. OBJECTIVES: The goal of this study was to determine the association between medication adherence levels and long-term MACE in these patients. METHODS: We queried the claims database of a large health insurer for patients hospitalized for MI or with ATH. The primary outcome measure was a composite of all-cause death, MI, stroke, or coronary revascularization. Using proportion of days covered for statins and angiotensin-converting enzyme inhibitors, patients were stratified as fully adherent (≥80%), partially adherent (≥40% to ≤79%), or nonadherent (<40%). Per-patient annual direct medical (ADM) costs were estimated by using unit costs from 2 national files. RESULTS: Data were analyzed for 4,015 post-MI patients and 12,976 patients with ATH. In the post-MI cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (18.9% vs. 26.3%; hazard ratio [HR]: 0.73; p = 0.0004) and partially adherent (18.9% vs. 24.7%; HR: 0.81; p = 0.02) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $369 and $440 compared with the partially adherent and nonadherent groups, respectively. In the ATH cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (8.42% vs. 17.17%; HR: 0.56; p < 0.0001) and the partially adherent (8.42% vs. 12.18%; HR: 0.76; p < 0.0001) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $371 and $907 compared with the partially adherent and nonadherent groups. CONCLUSIONS: Full adherence to guideline-recommended therapies was associated with a lower rate of MACE and cost savings, with a threshold effect at >80% adherence in the post-MI population; at least a 40% level of long-term adherence needs to be maintained to continue to accrue benefit. Novel approaches to improve adherence may significantly reduce cardiovascular events.

Cost-effectiveness and public health benefit of secondary cardiovascular disease prevention from improved adherence using a polypill in the UK.

OBJECTIVE: To evaluate the public health and economic benefits of adherence to a fixed-dose combination polypill for the secondary prevention of cardiovascular (CV) events in adults with a history of myocardial infarction (MI) in the UK. DESIGN: Markov-model-based cost-effectiveness analysis, informed by systematic reviews, which identified efficacy, utilities and adherence data inputs. SETTING: General practice in the UK. PARTICIPANTS: Patients with a mean age of 64.7 years, most of whom are men with a recent or non-recent diagnosis of MI and for whom secondary preventive medication is indicated and well tolerated. INTERVENTION: Fixed-dose combination polypill (100 mg aspirin, 20 mg atorvastatin and 2.5, 5, or 10 mg ramipril) compared with multiple monotherapy. PRIMARY AND SECONDARY OUTCOME MEASURES: CV events prevented per 1000 patients; cost per life-year gained; and cost per quality-adjusted life-year (QALY) gained. RESULTS: The model estimates that for each 10% increase in adherence, an additional 6.7% fatal and non-fatal CV events can be prevented. In the base case, over 10 years, the polypill would improve adherence by ∼20% and thereby prevent 47 of 323 (15%) fatal and non-fatal CV events per 1000 patients compared with multiple monotherapy, with an incremental cost-effectiveness ratio (ICER) of £8200 per QALY gained. Probabilistic sensitivity analyses for the base-case assumptions showed an 81.5% chance of the polypill being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained compared with multiple monotherapy. In scenario analyses that varied structural assumptions, ICERs ranged between cost saving and £21,430 per QALY gained. CONCLUSIONS: Assuming that some 450,000 adults are at risk of MI, a 10 percentage point uptake of the polypill could prevent 3260 CV events and 590 CV deaths over a decade.The polypill appears to be a cost-effective strategy to prevent fatal and non-fatal CV events in the UK.

Ozenoxacin 1% cream in the treatment of impetigo: a multicenter, randomized, placebo- and retapamulin-controlled clinical trial.

AIM: We compared the efficacy and safety of ozenoxacin (a new nonfluorinated quinolone) 1% cream with placebo in the treatment of impetigo. PATIENTS & METHODS: In a randomized, double-blind, multicenter study, patients received ozenoxacin cream or placebo cream twice daily for 5 days (a third group received retapamulin 1% ointment as a control). Clinical, microbiological and laboratory evaluations were performed during follow-up (over 2 weeks). RESULTS: Ozenoxacin was superior to placebo (success rate 34.8 vs 19.2%; p = 0.003). Microbiological success was 70.8% for ozenoxacin and 38.2% for placebo after 3-4 days and 79.2% versus 56.6% after 6-7 days. Ozenoxacin produced more rapid microbiological clearance than retapamulin. All treatments were well tolerated. CONCLUSION: Ozenoxacin 1% cream was effective and safe in the treatment of impetigo.

Characterization of variables that may influence ozenoxacin in susceptibility testing, including MIC and MBC values.

Ozenoxacin is a new des-fluoro-(6)-quinolone active against pathogens involved in skin and skin structure infections, including Gram-positives resistant to fluoroquinolones. The in vitro bacteriostatic and bactericidal activity of ozenoxacin, ciprofloxacin, and levofloxacin was studied against 40 clinical isolates and 16 ATCC quality control strains under different test conditions, including cation supplementation, pH, inoculum size, inoculum preparation, incubation time, human serum, and CO2 incubation. The activity of ozenoxacin was unaffected by cation test medium supplementation, inoculum preparation, incubation time, and the increasing CO2 environment. On the contrary, ozenoxacin activity decreased by high inoculum (10(7) CFU/mL), increased presence of human serum in the medium, and increased pH. The last effect was different for ciprofloxacin and levofloxacin, which decreased activity when pH decreased. The bactericidal mode of action of ozenoxacin and control drugs was consistently maintained (MBC/MIC ratios ≤4) in spite of variations of their activity under different test conditions.

[Cost-effectiveness of an intervention based on the Global INitiative for Asthma (GINA) recommendations using a computerized clinical decision support system: a physicians randomized trial]. / Coste-efectividad de una intervención basada en las recomendaciones de la Global INitiative for Asthma (GINA), mediante un sistema informatizado de apoyo a la decisión clínica: un ensayo con aleatorización de médicos.

BACKGROUND AND OBJECTIVE: To assess the cost-effectiveness of an intervention based on the Global INitiative for Asthma (GINA) recommendations as compared to usual care. SUBJECTS AND METHOD: Pragmatic, cluster-randomised trial. Ten pneumologists and 10 general practitioners were randomised to an intervention or control group, recruiting 98 and 100 asthma patients, respectively. The intervention consisted of an education program and a clinical decision support system (CDSS) providing recommendations based on the GINA. The control group was characterized by usual care. Effectiveness was assessed by the health related quality of life as measured by the St. George's Respiratory Questionnaire (SGRQ). Costs were computed from the resource consumption recorded during a 12 months follow-up period, and the cost-effectiveness of the intervention was investigated in an incremental analysis. RESULTS: The intervention effect on the SGRQ total score was estimated as a 6.8 point reduction (95% confidence interval, 2.5-11.1; p = 0.0021), and a significant improvement in the SGRQ subscores and in the symptoms-free periods were also observed. From the social perspective, the mean total costs showed savings of -1,022 Euros (95% confidence interval, -2,165 to 122; p = 0.0795) in intervention group as compared to usual care. The incremental analysis confirmed that the intervention was cost-effective. CONCLUSIONS: The implementation of an asthma management program based in GINA recommendations improved the patient's health related quality of life and was cost-effective as compared to usual care.

Coste-efectividad de una intervención basada en las recomendaciones de la Global INitiative for Asthma (GINA), mediante un sistema informatizado de apoyo a la decisión clínica: un ensayo con aleatorización de médicos / Cost-effectiveness of an intervention based on the Global INitiative for Asthma (GINA) recommendations using a computerized clinical decision support system: a physicians randomized trial

FUNDAMENTO Y OBJETIVO: Evaluar el coste-efectividad de una intervención basada en las recomendaciones de la Global INitiative for Asthma (GINA) comparada con la práctica clínica habitual. SUJETOS Y MÉTODO: Ensayo pragmático y aleatorizado por grupos. Se aleatorizó a los grupos de intervención y control a 10 neumólogos y 10 médicos de atención primaria, los cuales incluyeron a 98 y 100 pacientes asmáticos, respectivamente. La intervención consistió en facilitar a los médicos un sistema de ayuda a la decisión clínica (SADC) que ofrecía recomendaciones basadas en la GINA. Los médicos del grupo control no disponían de dicho SADC. La efectividad se determinó midiendo la calidad de vida por medio del St. Georges Respiratory Questionnaire(SGRQ). Se calcularon los costes a partir del consumo de recursos registrado durante 12 meses y se determinó el coste-efectividad de la intervención mediante un análisis incremental. RESULTADOS: El efecto de la intervención sobre la puntuación total del SGRQ se estimó en una reducción de 6,8 puntos (intervalo de confianza del 95%, 2,5-11,1; p = 0,0021) y en una mejora significativa en las subescalas, así como en los períodos libres de síntomas. Se observó una reducción de los costes en el grupo I de intervención, que se estimó en -1.022 € (intervalode confianza del 95%, -2.165 a 122; p = 0,0795) desde la perspectiva social. El análisis incremental confirmó el coste-efectividad de la intervención. CONCLUSIONES: La implementación de un programa de gestión del asma basado en recomendaciones de la GINA mejoró la calidad de vida de los pacientes y fue coste-efectiva respecto de la práctica clínica habitual

BACKGROUND AND OBJECTIVE: To assess the cost-effectiveness of an intervention based on the GlobalINitiative for Asthma (GINA) recomendations as compared to usual care. SUBJECTS AND METHOD: Pragmatic, cluster-randomised trial. Ten neumologysts and 10 generalpractitioners were randomised to an intervention or control group, recruiting 98 and 100 asth-mapatients, respectively. The intervention consisted of an education program and a clinical decision support system (CDSS) providing recommendations based on the GINA. The control group was characterized by usual care. Effectiveness was assessed by the health related quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ). Costs were computed from the resource consumption recorded during a 12 months follow-up period, and thecost-effectiveness of the intervention was investigated in an incremental analysis. RESULTS: The intervention effect on the SGRQ total score was estimated as a 6.8 point reduction(95% confidence interval, 2.5-11.1; p = 0.0021), and a significant improvement in the SGRQ subscores and in the symptoms-free periods were also observed. From the social perspective, the mean total costs showed savings of -1,022 € (95% confidence interval, -2,165 to122; p = 0.0795) in intervention group as compared to usual care. The incremental analysis confirmed that the intervention was cost-effective. CONCLUSIONS: The implementation of an asthma management program based in GINA recommendations improved the patient’s health related quality of life and was cost-effective as compared to usual care

Métodos utilizados para realizar evaluaciones económicas de intervenciones sanitarias / Methods to perform economic assessments of health interventions

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Evaluación económica en medicina / Economic assessment in medicine

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Estudios farmacogenéticos: guía de evaluación para Comités Éticos de Investigación Clínica. Protocolo y hoja de información al paciente (II) / Pharmacogenetic studies: evaluation guidelines for research ethics committees. Study protocol and patient information sheet (II)

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Estudios farmacogenéticos: guía de evaluación para comités éticos de investigación clínica. Fundamentos científicos y marco legal (I) / Pharmacogenetic studies: evaluation guidelines for research ethics committees. Scientific background and legal framework (I)

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¿larga vida para la última actualización de la Declaración de Helsinki? / Long life for the latest update on Declaration of Helsinki?

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Propuesta de aplicación de la ley de protección de datos de carácter personal en las hojas de información y consentimiento de los participantes en los ensayos clínicos / Proposal for the application of the Law of Data Protection in informed consent formularies from clinical trials in Spain

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La Declaración de Helsinki, ¿traduttore traditore? / Declaration of Helsinki, Traduttore traditiore?

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Diferencias entre las versiones en español y en inglés de la última actualización de la Declaración de Helsinki / Differences between the Spanish and English versions of the last update of the Helsinki Declaration

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