Efficacy and Safety of Calcifediol in Young Adults with Vitamin D Deficiency: A Phase I, Multicentre, Clinical Trial-POSCAL Study.

Vitamin D deficiency is highly prevalent, and recent evidence suggests a possible association between vitamin D deficiency and various health conditions. The aim of this study was to assess monthly calcifediol treatments for vitamin D deficiency (or biweekly, if the deficiency was severe) in a young adult population with no associated comorbidities. This multicentre phase I trial started with a four month open-label treatment phase (TP) that included 101 participants (65% women with mean age 29.8 years). Eighty-two percent of the subjects (79/96) achieved 25(OH)D levels within the target range (20-60 ng/mL) by the end of the TP, and they were subsequently randomised and subjected to a double-blind, placebo-controlled, five month follow-up phase (FP). At the end of the FP, 89% of participants maintained vitamin D levels of >20 ng/mL with calcifediol, versus 49% with placebo (p < 0.001). Subjects receiving monthly calcifediol during both phases (n = 32) maintained 25(OH)D levels >20 ng/mL, whereas those on the placebo during the FP (n = 38) exhibited deficiency levels of 25(OH)D by the end of the study. No clinically relevant changes in bone metabolism parameters or toxic 25(OH)D levels were observed, and no serious adverse events were reported throughout the study. Calcifediol is a safe and effective treatment for vitamin D deficiency in the young adult population, but long-term use may be required to sustain optimal 25(OH)D levels.

The Challenges of Vaccine Trial Participation among Underserved and Hard-to-Reach Communities: An Internal Expert Consultation of the VACCELERATE Consortium.

Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within-and across-countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.

Immunogenicity and reactogenicity of a first booster with BNT162b2 or full-dose mRNA-1273: A randomised VACCELERATE trial in adults ≥75 years (EU-COVAT-1).

BACKGROUND: Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially for people of advanced age, however, optimal dosing regimens are as yet lacking. METHODS: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days. RESULTS: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants. INTERPRETATION: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years. FUNDING: This trial was funded by the European Commission (Framework Program HORIZON 2020).

VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe.

BACKGROUND: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. METHODS: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. RESULTS: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. CONCLUSIONS: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.

Enhancing Public Health Communication Regarding Vaccine Trials: Design and Development of the Pan-European VACCELERATE Toolkit.

BACKGROUND: The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial-related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. OBJECTIVE: This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. METHODS: Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients' Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. RESULTS: This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. CONCLUSIONS: The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents' concerns for potential participation of children in vaccine trials.

A multinational, phase 2, randomised, adaptive protocol to evaluate immunogenicity and reactogenicity of different COVID-19 vaccines in adults ≥75 already vaccinated against SARS-CoV-2 (EU-COVAT-1-AGED): a trial conducted within the VACCELERATE network.

BACKGROUND: In the ongoing COVID-19 pandemic, advanced age is a risk factor for a severe clinical course of SARS-CoV-2 infection. Thus, older people may benefit in particular from booster doses with potent vaccines and research should focus on optimal vaccination schedules. In addition to each individual's medical history, immunosenescence warrants further research in this population. This study investigates vaccine-induced immune response over 1 year. METHODS/DESIGN: EU-COVAT-1-AGED is a randomised controlled, adaptive, multicentre phase II protocol evaluating different booster strategies in individuals aged ≥75 years (n=600) already vaccinated against SARS-CoV-2. The initial protocol foresaw a 3rd vaccination (1st booster) as study intervention. The present modified Part B of this trial foresees testing of mRNA-1273 (Spikevax®) vs. BNT162b2 (Comirnaty®) as 4th vaccination dose (2nd booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants. The primary endpoint of the trial is to assess the rate of 2-fold antibody titre increase 14 days after vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. Secondary endpoints include the changes in neutralising antibody titres (Virus Neutralisation Assay) against wild-type as well as against Variants of Concern (VOC) at 14 days and up to 12 months. T cell response measured by qPCR will be performed in subgroups at 14 days as exploratory endpoint. Biobanking samples are being collected for neutralising antibody titres against potential future VOC. Furthermore, potential correlates between humoral immune response, T cell response and neutralising capacity will be assessed. The primary endpoint analysis will be triggered as soon as for all patients the primary endpoint (14 days after the 4th vaccination dose) has been observed. DISCUSSION: The EU-COVAT-1-AGED trial Part B compares immunogenicity and safety of mRNA-1273 (Spikevax®) and BNT162b2 (Comirnaty®) as 4th SARS-CoV-2 vaccine dose in adults ≥75 years of age. The findings of this trial have the potential to optimise the COVID-19 vaccination strategy for this at-risk population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05160766 . Registered on 16 December 2021. PROTOCOL VERSION: V06_0: 27 July 2022.

VACCELERATE Volunteer Registry: A European study participant database to facilitate clinical trial enrolment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has evidenced the key role of vaccine design, obtention, production and administration to successfully fight against infectious diseases and to provide efficient remedies for the citizens. Although clinical trials were rapidly established during this pandemic, identifying suitable study subjects can be challenging. For this reason, the University Hospital Cologne established a volunteer registry for participation in clinical trials first in Germany, which has now been incorporated into the European VACCELERATE clinical trials network and grew to a European Volunteer Registry. As such, VACCELERATE's Volunteer Registry aims to become a common entry point for potential volunteers in future clinical trials in Europe. METHODS: Interested volunteers who would like to register for clinical trials in the VACCELERATE Volunteer Registry can access the registration questionnaire via http://www.vaccelerate.eu/volunteer-registry. Potential volunteers are requested to provide their current country and area of residence, contact information, including first and last name and e-mail address, age, gender, comorbidities, previous SARS-CoV-2 infection and vaccination status, and maximum distance willing to travel to a clinical trial site. The registry is open to both adults and children, complying with national legal consent requirements. RESULTS: As of May 2022, the questionnaire is available in 12 countries and 14 languages. Up to date, more than 36,000 volunteers have registered, mainly from Germany. Within the first year since its establishment, the VACCELERATE Volunteer Registry has matched more than 15,000 volunteers to clinical trials. The VACCELERATE Volunteer Registry will be launched in further European countries in the coming months. CONCLUSIONS: The VACCELERATE Volunteer Registry is an active single-entry point for European residents interested in COVID-19 clinical trials participation in 12 countries (i.e., Austria, Cyprus, Germany, Greece, Ireland, Lithuania, Norway, Portugal, Spain, Sweden and Turkey). To date, more than 15,000 registered individuals have been connected to clinical trials in Germany alone. The registry is currently in the implementation phase in 5 additional countries (i.e., Belgium, Czech Republic, Hungary, Israel and the Netherlands).

Health Care Workers' Reasons for Choosing Between Two Different COVID-19 Prophylaxis Trials in an Acute Pandemic Context: Single-Center Questionnaire Study.

BACKGROUND: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). OBJECTIVE: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. METHODS: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. RESULTS: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). CONCLUSIONS: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

Prevalencia de factores de riesgo cardiovascular en trabajadores de un hospital terciario de Madrid / Alterations of sensitivity to contrast and stereopsis in workers exposed to aromatic hydrocarbons

Las enfermedades cardiovasculares son la principal causa de muerte a nivel mundial y en España. El objetivo de este estudio fue evaluar los FRCV clásicos modificables en una muestra de trabajadores del Hospital Universitario La Paz (HULP) con relación a la categoría profesional, edad, sexo, así como estimar el riesgo cardiovascular según el modelo SCORE para los trabajadores ≥ 40 años y con el Riesgo Relativo (RR) en menores de 40 años. MATERIAL Y MÉTODOS: Se realizó un estudio observacional descriptivo retrospectivo con un análisis de variables de FRCV en una muestra de 687 trabajadores del HULP de Madrid durante 2016. Se recogieron variables clínicas, antropométricas y sociodemográficas. Para el análisis comparativo, se aplicó la prueba de Chi-cuadrado de Pearson o el test exacto de Fisher para las variables cualitativas, mientras que la prueba de Kruskal-Wallis se usó para determinar la asociación entre variables cuantitativas y cualitativas. El riesgo cardiovascular se determinó mediante el baremo SCORE y el RR. RESULTADOS: La muestra fue de 687 trabajadores (70,8% mujeres, y 29,2% hombres). La prevalencia de tabaquismo fue del 21%, no fumadores (60%) y exfumadores (19%). Dislipemia: 58,8%. Hipertensión arterial: 24,3%. Inactividad física: 35,7%, con 3,8 ± 2 horas semanales de ejercicio físico. Obesidad/sobrepeso: 36,5%. DM: 4,5%. Alcohol: 37,8%. En el cálculo del riesgo cardiovascular se encontró un SCORE alto/muy alto: 15,2% y RR = 1 (83%), RR = 2 (16%) y RR = 3 (1%). CONCLUSIONES: Se halló una elevada prevalencia de FRCV en los sujetos que acuden a realizarse el examen de salud, similar a la hallada en otros estudios consultados con poblaciones laborales y no laborales. Se encontró mayor prevalencia de factores de riesgo modificables en personal de gestión y servicios y en técnicos sanitarios que en diplomados y licenciados sanitarios. Y conforme al aumento de edad y en el sexo masculino

OBJECTIVE: Cardiovascular diseases are the first cause of death worldwide and in Spain. The objective of this study was to research the classic cardiovascular risk factors (CVRF) in a population in Madrid Hospital La Paz by professional category, age and gender as well as to estimate the cardiovascular risk using the SCORE model for workers ≥ 40 years and with Relative Risk (RR) for under 40 years. MATERIAL AND METHODS: A descriptive observational retrospective study was carried out with a CVRF variables analysis in a 687 workers population at the Madrid HULP in 2016. Clinical, anthropometric, and sociodemographic variables were gathered. For the comparative analysis, Pearson's Chi-squared or Fisher exact test were applied for the qualitative variables, and Kruskal-Wallis was used to determine the association between qualitative and quantitative variables. Cardiovascular risk was determined by SCORE and RR. RESULTS: The sample was 687 workers (70,8% women and 29,2% men). Smoking prevalence was 21%, non-smoking (60%) and former smokers (19%). Dyslipidaemia: 58,8%. Arterial hypertension: 24,3%. Physical inactivity: 35,7%, with 3,8 ± 2 hours/week of physical exercise. Obesity/overweigh:36,5%. DM: 4,5%. Alcohol: 37,8%. Cardiovascular risk calculation was determined by SCORE high/very high: 15,2% and RR = 1 (83%), RR = 2 (16%) and RR = 3 (1%). CONCLUSIONS: A high CVRF prevalence was found in the subjects that came to the health surveillance screening, similar at the one in occupational and non-occupational studies that has been consulted. A higher prevalence of modifiable risk factors was found in management and services personnel and in medical technicians than in healthcare university graduates. And more as the age increases and in male gender

Estrategias de promoción de la salud para disminuir el riesgo cardiovascular de los trabajadores del ámbito hospitalario público de la Comunidad de Madrid / Health promotion strategies to reduce cardiovascular risk in workers at Comunidad de Madrid public hospitals

OBJETIVOS: La enfermedad cardiovascular es consecuencia en muchos casos de hábitos poco saludables, y la promoción de la salud en el trabajo incluye la realización de una serie de políticas y actividades diseñadas para ayudar a trabajadores a aumentar el control sobre su salud y a mejorarla. El objetivo de este estudio fue evaluar las estrategias de promoción de la salud cardiovascular realizadas en hospitales públicos de la Comunidad de Madrid para poder implementar en un futuro mejoras en las áreas más deficientes. Material y MÉTODOS: Se realizó un estudio observacional descriptivo prospectivo mediante una encuesta vía email a 10 hospitales públicos de la Comunidad de Madrid. Se utilizó el cuestionario Move Europe facilitado por el INSST. La descripción de las variables cualitativas se realizó con la frecuencia absoluta y porcentajes. RESULTADOS: La tasa de respuesta de los centros en la encuesta fue del 100%. Se encontró un muy bajo porcentaje de hospitales que alcanzasen la puntuación de "buenas prácticas" en las diferentes áreas estudiadas: "Política y Cultura" (40%), "Tabaquismo" (50%), "Alimentación" (10%), "Ejercicio Físico" (0%) y "Estrés" (0%). Un solo hospital obtuvo consideración de buenas prácticas en tres áreas, dos hospitales en dos áreas, tres hospitales en un área y cuatro no obtuvieron dicha clasificación en ningún área. CONCLUSIONES: Las estrategias de promoción de la salud implantadas en los hospitales de la Comunidad de Madrid encuestados son insuficientes en todas las áreas evaluadas. Se puede considerar que en todas estas materias se podría empezar por realizar estrategias de mejora, especialmente en "Ejercicio Físico", "Estrés" y "Alimentación" que son las más deficientes

OBJECTIVES: Cardiovascular disease is often caused by bad habits, and health promotion at work includes policies and activities designed to help workers control their own health and improve it. The objective of this study was the research of health promotion strategies in Comunidad de Madrid public hospitals to make improvements in the future in the areas with deficient results. MATERIAL AND METHODS: A descriptive observational prospective study was carried out with a email survey at 10 public hospitals in Comunidad de Madrid. The questionnaire that was used is the Move Europe available in Spanish at the INSST web page. Qualitative variables description was done with absolute frequency and percentages. RESULTS: The survey response rate was 100%. A very low percentage of centres that reached "good practices" was found: "Policy and Culture" (40%), "Smoking" (50%), "Nutrition" (10%), "Physical Activity" (0%) and "Stress" (0%). Only one hospital obtained "good practices" consideration in three areas, two hospitals in two areas, three hospitals in one area, and four of them didn't obtain that classification in any of the areas. CONCLUSIONS: The health promotion strategies implemented in the evaluated Comunidad de Madrid hospitals are not enough in all the studied areas. It can be considered that in all of this matters it could be possible to start strategies to promote improvement of them, especially in "Physical Activity", "Stress" y "Nutrition" that are the most deficient

Desarrollo de un cuestionario dirigido a conocer el proceso de consentimiento informado en investigación clínica desde la perspectiva del paciente / Informed consent process in clinical trials: development of a patient-reported questionnaire

OBJETIVO: Desarrollar un cuestionario en español dirigido a evaluar el proceso de información y obtención del consentimiento informado en investigación clínica desde la perspectiva del paciente. Con esta herramienta se pretende analizar en los pacientes que participan en un ensayo clínico los siguientes aspectos: la experiencia y desarrollo práctico del proceso de consentimiento informado, su nivel de satisfacción con dicho proceso y su nivel de comprensión del estudio. MÉTODO: Estudio de desarrollo, adaptación y validación de un cuestionario autocumplimentable para evaluar el proceso de consentimiento informado a través de la información obtenida de los pacientes. Los pasos seguidos fueron: revisión bibliográfica, generación de un pool de ítems, redacción del cuestionario, revisión por expertos, pilotaje, optimización y análisis de legibilidad. También se realizó una evaluación, selección, traducción y adaptación al español de una herramienta disponible en lengua inglesa que permitiese valorar la comprensión del paciente de la información. RESULTADOS: El cuestionario quedó conformado por cuatro apartados que permiten evaluar: 1) datos sociodemográficos, 2) aspectos prácticos relacionados con el desarrollo del proceso de consentimiento informado, 3) valoración del paciente del proceso (satisfacción, expectativas y motivaciones), 4) grado de comprensión. Para valorar la comprensión se seleccionó el cuestionario Quality of Informed Consent questionnaire, que fue traducido por tres traductores bilingües. Se incluyeron tres preguntas adicionales para evaluar la comprensión de conceptos relacionados con el equívoco terapéutico y el enmascaramiento de los tratamientos. La validez de contenido fue evaluada mediante consulta con un panel de expertos. En el análisis de legibilidad se obtuvo un valor de Índice de Flesch-Szigriszt de 64,34 equivalente a un grado de dificultad "normal" en la escala Inflesz. En el estudio piloto se entrevistó a 32 pacientes que mostraron no tener dificultades para comprender las preguntas ni problemas a la hora de utilizar las escalas de respuesta. El tiempo medio de cumplimentación del cuestionario fue de 16,6 minutos. CONCLUSIONES: La herramienta desarrollada es útil a la hora de conocer y valorar el proceso de consentimiento informado desde la perspectiva del paciente al que se le invita a participar en un estudio. Su aplicación podría resultar de ayuda a los investigadores para verificar que se ha seguido un adecuado proceso y para identificar aspectos concretos que son susceptibles de ser modificados y optimizados

OBJECTIVE: To develop a Spanish-language questionnaire aimed at evaluating patients' perception of the way they are briefed and their consent is obtained prior to participating in clinical trials. The tool was conceived to evaluate the following aspects: patients' personal experience, the way the informed consent process was implemented in practice, patients' level of satisfaction with the process, and their level of understanding of the study itself. METHOD: This study looked into the development, adaptation and validation of a self-administered questionnaire intended to evaluate the informed consent process on the basis of information provided by respondents. The steps followed included: literature review, generation of an items pool, drawing up of the questionnaire, expert review, piloting, and reading ease optimization and analysis. A commonly-used English-language questionnaire was evaluated, translated into Spanish and adapted so as to determine the extent to which subjects understood the information conveyed to them. RESULTS: In its final version, the questionnaire came to comprise four sections intended to evaluate: 1) socio-demographic data; 2) practical aspects related with the development of the informed consent process; 3) patients' perception of the process (satisfaction, expectations and motivations); and 4) their level of understanding. Understanding was gaged using the QuIC questionnaire, translated by three bilingual translators. Additional questions were included to evaluate the understanding of concepts related with blinding and therapeutic misconception. The validity of the contents was evaluated by consulting with an expert panel. The reading ease analysis yielded an IFSZ score of 64.34, equivalent to an "average difficulty" grade on the Inflesz scale. In the pilot study, interviews were held with 32 patients, who did not appear to have any difficulties in understanding the questions asked of them or in using Likert-type scales to respond. Mean completion time was 16.6 minutes. CONCLUSIONS: The tool developed as part of this study has shown itself capable of providing an understanding and an assessment of the informed consent process from the perspective of a patient who is invited to participate in a clinical trial. Implementation of the questionnaire could help investigators ascertain that the process has been correctly executed and identify specific aspects that may require to be changed or optimized

Informed consent process in clinical trials: development of a patient-reported questionnaire.

OBJECTIVE: To develop a Spanish-language questionnaire aimed at  evaluating patients' perception of the way they are briefed and their  consent is obtained prior to participating in clinical trials. The tool was  conceived to evaluate the following aspects: patients' personal experience,  the way the informed consent process was implemented in practice,  patients' level of satisfaction with the process, and their level of  understanding of the study itself. METHOD: This study looked into the development, adaptation and  validation of a self-administered questionnaire intended to evaluate the  informed consent process on the basis of information provided by  respondents. The steps followed included: literature review, generation of  an items pool, drawing up of the questionnaire, expert review, piloting, and reading ease optimization and analysis. A commonly-used English- language questionnaire was evaluated, translated into Spanish and  adapted so as to determine the extent to which subjects understood the  information conveyed to them. RESULTS: In its final version, the questionnaire came to comprise four sections intended to evaluate: 1) socio-demographic data; 2) practical aspects related with the development of the informed consent  process; 3) patients' perception of the process (satisfaction, expectations  and motivations); and 4) their level of understanding. Understanding was gaged using the QuIC questionnaire, translated by three bilingual  translators. Additional questions were included to evaluate the  understanding of concepts related with blinding and therapeutic  misconception. The validity of the contents was evaluated by consulting  with an expert panel. The reading ease analysis yielded an IFSZ score of  64.34, equivalent to an "average difficulty" grade on the Inflesz scale. In  the pilot study, interviews were held with 32 patients, who did not appear to have any difficulties in understanding the questions asked of  them or in using Likert-type scales to respond. Mean completion time was 16.6 minutes. CONCLUSIONS: The tool developed as part of this study has shown itself capable of providing an understanding and an assessment of the  informed consent process from the perspective of a patient who is invited  to participate in a clinical trial. Implementation of the questionnaire could help investigators ascertain that the process has been correctly  executed and identify specific aspects that may require to be changed or  optimized.

Objetivo: Desarrollar un cuestionario en español dirigido a evaluar el proceso de información y obtención del consentimiento informado en  investigación clínica desde la perspectiva del paciente. Con esta  herramienta se pretende analizar en los pacientes que participan en un  ensayo clínico los siguientes aspectos: la experiencia y desarrollo práctico  del proceso de consentimiento informado, su nivel de satisfacción con  dicho proceso y su nivel de comprensión del estudio.Método: Estudio de desarrollo, adaptación y validación de un cuestionario autocumplimentable para evaluar el proceso de  consentimiento informado a través de la información obtenida de los  pacientes. Los pasos seguidos fueron: revisión bibliográfica, generación de  un pool de ítems, redacción del cuestionario, revisión por expertos,  pilotaje, optimización y análisis de legibilidad. También se realizó una  evaluación, selección, traducción y adaptación al español de una  herramienta disponible en lengua inglesa que permitiese valorar la  comprensión del paciente de la información.Resultados: El cuestionario quedó conformado por cuatro apartados que  permiten evaluar: 1) datos sociodemográficos, 2) aspectos prácticos relacionados con el desarrollo del proceso de consentimiento  informado, 3) valoración del paciente del proceso (satisfacción,  expectativas y motivaciones), 4) grado de comprensión. Para valorar la  comprensión se seleccionó el cuestionario Quality of Informed Consent  questionnaire, que fue traducido por tres traductores bilingües. Se  incluyeron tres preguntas adicionales para evaluar la comprensión de  conceptos relacionados con el equívoco terapéutico y el enmascaramiento  de los tratamientos. La validez de contenido fue evaluada mediante  consulta con un panel de expertos. En el análisis de legibilidad se obtuvo  un valor de Índice de Flesch-Szigriszt de 64,34 equivalente a un grado de  dificultad "normal" en la escala Inflesz. En el estudio piloto se entrevistó a  32 pacientes que mostraron no tener dificultades para comprender las  preguntas ni problemas a la hora de utilizar las escalas de respuesta. El  tiempo medio de cumplimentación del cuestionario fue de 16,6 minutos.Conclusiones: La herramienta desarrollada es útil a la hora de conocer y  valorar el proceso de consentimiento informado desde la perspectiva del  paciente al que se le invita a participar en un estudio. Su aplicación podría  resultar de ayuda a los investigadores para verificar que se ha seguido un  adecuado proceso y para identificar aspectos concretos que son  susceptibles de ser modificados y optimizados.

Randomised multicentre clinical trial to evaluate voriconazole pre-emptive genotyping strategy in patients with risk of aspergillosis: vorigenipharm study protocol.

INTRODUCTION: Invasive aspergillosis is the most important cause of morbidity and mortality in patients with haematological diseases. At present, voriconazole is the first-line treatment for invasive fungal disease. The pharmacokinetic interindividual variability of voriconazole depends on genetic factors. CYP450 is involved in 70%-75% of total metabolism of voriconazole, mainly CYP3A4 and CYP2C19, with the remaining 25%-30% of metabolism conducted by monooxygenase flavins. CYP2C19 single nucleotide polymorphisms could explain 50%-55% of variability in voriconazole metabolism. MATERIALS AND METHODS: The main objective is to compare efficiency of pre-emptive voriconazole genotyping with routine practice. The primary outcome is serum voriconazole on the fifth day within the therapeutic range. The secondary outcome is the combined variables of therapeutic failure and adverse events within 90 days of first administration, associated with voriconazole. A total of 146 patients at risk of invasive aspergillosis who will potentially receive voriconazole will be recruited, and CYP2C19 will be genotyped. If the patient ultimately receives voriconazole, they will be randomised (1:1 experimental/control). In the experimental arm, patients will receive a dose according to a pharmacogenetic algorithm, including CYP2C19 genotype and clinical and demographic information. In the control arm, patients will receive a dose according to clinical practice guidelines. In addition, a Spanish National Healthcare System (NHS) point-of-view cost-effectiveness evaluation will be performed. Direct cost calculations for each arm will be performed. CONCLUSION: This trial will provide information about the viability and cost-effectiveness of the implementation of a pre-emptive voriconazole genotyping strategy in the Spanish NHS. ETHICS AND DISSEMINATION: A Spanish version of this protocol has been evaluated and approved by the La Paz University Hospital Ethics Committee and the Spanish Agency of Medicines and Medical Devices. Trial results will be submitted for publication in an open peer-reviewed medical speciality-specific publication. TRIAL REGISTRATION NUMBER: Eudra-CT: 2019-000376-41 and NCT04238884; Pre-results.

Study on the conditions of use for Caribán(R) and other antiemetics in the treatment of nausea and vomiting during pregnancy / Estudio sobre las condiciones de uso de Caribán(R) y de otros antieméticos en el tratamiento de las náuseas y vómitos en el embarazo: estudio prospectivo observacional longitudinal

Objective: We performed a prospective observational study on the conditions of use of a medication, Caribán(R), and of other antiemetics for the treatment of nausea and vomiting in pregnancy (NVP). The study was practical in design, and its main objective was to determine the frequency of use of Caribán(R) in the treatment of NVP by analyzing conditions of use in daily clinical practice. Material and methods: The study population comprised 184 pregnant women with nausea and/or vomiting during the days preceding the first study visit. The patients attended up to 4 visits, 3 of which were face-to-face, and provided clinical follow-up data and data on the treatment used by means of an app. Data on treatment and the evaluation of nausea and vomiting were obtained every 24 hours using the Pregnancy-Unique Quantification of Emesis and Nausea score (PUQE). Results: The most frequently used initial regimen was 1 capsule every 8 hours. Data were available from the baseline visit and from the daily follow-up of 158 women (ie, 4982 daily evaluations). The mean score for severity of NVP was 5.69 points (mild) (SD, 1.8; range, 3-13) and the mean cumulative dose per woman throughout the follow-up was 34.61 capsules (6-197). NVP was mild in 72.48% of evaluations, moderate in 26.57%, and severe in 0.94%. Patients did not take medication in 54% (n=1969) of the mild daily episodes and in 14% of the moderate episodes. Mean consumption per daily episode was 1.74 (0-10) capsules per episode of mild NVP and 2.14 (0-35) capsules per episode of moderate NVP. Women who had NVP took Caribán(R) according to the app on 66.7% of the days with symptoms. Conclusions: The most common initial regimen prescribed was 1 capsule every 8 hours. Most of the episodes of NVP were mild, and on 50.85% of days with mild NVP, the women did not take medication. The mean daily dose per mild episode was 1.74 capsules. The patients reported having taken medication for moderate NVP in 86% of cases. The mean dose per episode was 2.14 capsules. The patients took Caribán(R) on 66.7% of days with NVP

Objetivo: El estudio sobre las condiciones de uso de Caribán(R) y otros antieméticos en el tratamiento de las náuseas y vómitos del embarazo (NVE) es un estudio observacional prospectivo de utilización de medicamentos diseñado con criterios pragmáticos que se plantea con el objetivo principal de determinar la frecuencia de uso de Caribán(R) en el tratamiento de las náuseas y vómitos del embarazo (NVE) analizando sus condiciones de uso en la práctica clínica diaria. Material y Metodos: Han participado 184 embarazadas con náuseas y/o vómitos en los días previos a la primera visita del estudio que atendieron hasta 4 visitas, tres de ellas presenciales, y facilitaron información del seguimiento clínico y del tratamiento utilizado mediante una aplicación telefónica. Se han recogido variables de tratamiento y la valoración de náuseas y vómitos cada 24 horas mediante la escala PUQE (PregnancyUniqueQuantification of Emesis and nausea). Resultados: La pauta de inicio más frecuentemente utilizada fue una capsula cada 8 horas. Existen datos de visita basal y de seguimiento diario de 158 embarazadas que suponen 4982 valoraciones diarias. La valoración media de la gravedad de las NVE es 5,69 puntos (LEVE), (SD 1,8, rango 3-13) y la dosis acumulada media por mujer durante todo el seguimiento 34,61 cápsulas ( 6-197). En el 72,48% de todas las valoraciones las NVE fueron leves, el 26,57% moderadas y el 0,94% graves. En el 54% (n=1969) de los episodios diarios leves y en el 14% de los moderados las gestantes no tomaron medicación. El consumo medio por cada episodio diario de NVE leve fue de 1,74 (0-10) cápsulas, mientras que en cada episodio moderado se utilizaron 2,14 (0-35) cápsulas. Las mujeres que tenían NVE tomaban Caribán(R) según la aplicación en el 66,7% de los días que tenían clínica. Conclusiones: La pauta de inicio prescrita mas frecuentemente fue una capsula cada 8 horas. La mayor parte de los episodios de NVE son leves, y en el 50.85% de los días con náuseas o vómitos leves las embarazadas no tomaron medicación. La dosis media por episodio/día leve es de 1,74 cápsulas. En los episodios diarios de NVE moderados el 86% de las embarazadas señalaron tomar la medicación siendo la dosis media por episodio de 2,14. El 66,7% de los días en que las mujeres tenían NVE tomaban Caribán(R)

Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.

The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.

¿Hay diferencias entre las gonadotropinas disponibles para la estimulación ovárica en técnicas de reproducción asistida? / Are there any differences in the gonadotrophins available for ovarian stimulation in assisted reproduction techniques?

En el mercado español se dispone de diversas gonadotropinas utilizadas en los programas de reproducción asistida. El objetivo de esta revisión es determinar las diferencias entre ellas y establecer las ventajas y los inconvenientes de cada una en base a su origen, seguridad y eficacia clínica. Desde el punto de vista técnico, las gonadotropinas recombinantes presentan ventajas técnicas y mayor pureza, actividad específica y homogeneidad entre lotes. Desde el punto de vista de la seguridad, aunque hay diferencias claras en el origen, y por tanto en los riesgos de transmisión de enfermedad infecciosa, todas las gonadotropinas disponibles han mostrado ser seguras. Es desde el punto de vista de la eficacia donde es más difícil establecer diferencias. Muchos de los estudios disponibles son pequeños y no siempre los parámetros de evaluación han sido comparables. La mayoría de los estudios no han podido establecer diferencias, por lo que existen en la literatura científica diversos metaanálisis que tratan de responder básicamente a dos aproximaciones: saber si las FSH recombinantes (FSHr) son mejores que las urinarias y si la hormona recombinante es mejor que la gonadotropina menopáusica humana. Los datos no permiten demostrar que las urinarias o la hMG, solas o en combinación, sean más eficaces que la FSHr, mientras que, por el contrario, las recombinantes han mostrado ser más eficaces que las urinarias purificadas agrupadas (AU)

In Spain, several different gonadotrophins are available for assisted reproductive techniques. The present review aims to determine the differences between these gonadotrophins and to establish the advantages and limitations of each in terms of their origin, safety, and efficacy. From the technical point of view, recombinant gonadotrophins have enhanced purity, specific activity and greater consistency. From the safety point of view, there are clear differences in the origin and manufacturing process and consequently in the risk of infectious diseases; however, to date, all gonadotropins have been demonstrated to be safe. Differences in efficacy are more difficult to establish. Many trials have compared preparations but, because of their small size and variations in study design, the results have been variable. Most of the studies have failed to detect any differences and consequently several meta-analyses have aimed to determine whether recombinant follicle- stimulating hormone (FSH) gonadotrophins are preferable to urinary-derived FSH and whether recombinant hormone is superior to human menopausal gonadotropin (hMG). The published results do not demonstrate that urinary-derived FSH or hMG, alone or when data are pooled, are more effective than recombinant FSH. In contrast, recombinant gonadotrophins have been shown to be more effective than urinary- derived gonadotrophins as a whole (AU)