4.2 Rationale and Background:
Oestrogen deficiency, described as a decline in the levels of circulating oestrogens, affects numerous tissues in postmenopausal women, including musculoskeletal, vascular, and urogenital systems (Archer 2010).
Oestrogen deficiency leads to a decrease in vaginal lubrication, which is an early hallmark of vulvar and vaginal atrophy (VVA). Symptoms of VVA include vaginal dryness, burning/itching, dyspareunia, vulvar pruritus, bleeding, particularly associated with sexual activity. VVA is also associated with urinary symptoms including urethral discomfort, frequency, haematuria, urinary tract infection, and dysuria (MacBride, Rhodes et al. 2010).
The prevalence of VVA ranges from 45%-57% (Levine, Williams et al. 2008, Santoro and Komi 2009). Current therapies include systemic oestrogens, local oestrogens and lubricants/moisturisers. Ospemifene is the first non-steroidal selective oestrogen receptor modulator (SERM) approved in the EU for the treatment of moderate to severe symptomatic vulvar and vaginal atrophy (VVA) in post-menopausal women who are not candidates for local vaginal oestrogen therapy .
The SERM class of drugs has been associated with an increased risk of venous thromboembolism (VTE) and cerebrovascular events (CVE). In the ospemifene clinical programme, which followed the Food and Drug Administration (FDA) Guidance for the Treatment of VVA, no increase in the incidence of VTE or CVE in the ospemifene cohort compared to placebo was observed. This Post-Authorisation Safety Study (PASS) is being undertaken to assess the safety of ospemifene in real life over a period of up to seven years in the US and five years in the European Union, EU, ( Spain, Italy and Germany). The PASS will involve comparative analyses between specified cohorts of women in the US and Germany arms of the study, and analyses of off-label use in the EU arms (Spain, Italy and Germany).
4.3 Research Question and Objectives:
Following is the research question of interest which is applicable to the Spain arm of the study:
What is the off-label use among ospemifene patients in Spain?
Additional questions of interest that are studied in other countries within the PASS include:
What is the incidence and risk of various side effects (such as VTE, CVE, endometrial hyperplasia, endometrial cancer, pelvic organ prolapse, urinary incontinence, gall bladder events, atrial fibrillation, renal failure, renal carcinoma, renal adenoma, liver tumours, thymic epithelial tumours, increased triglycerides, and vaginal bleeding) in a cohort of postmenopausal women newly prescribed ospemifene relative to (a) a cohort of postmenopausal women diagnosed with VVA but not treated for their condition with local or systemic oestrogens and (b) a cohort of postmenopausal women newly prescribed other SERM therapies (SERM comparison cohort) being utilised for oestrogen-deficiency conditions (i.e., non-cancer and non-infertility indications) or breast cancer prevention.
The objective of the study in Spain is to assess off-label use among ospemifene patients, including use in patients with vaginal bleeding or signs or symptoms of endometrial hyperplasia and endometrial cancer (contraindications)
4.4 Study Design:
The Spain arm of the PASS is an annual cross-sectional study using electronic medical records (EMR). This protocol addresses only the Spain database study arm, and summarises how off-label use of ospemifene will be investigated. All patients with at least one ospemifene prescription are eligible for the study
In order to minimise bias, new users (initiators) will be identified. A new user is defined as anyone in the database with at least 12 months of medical history and with at least one prescription of ospemifene. The study duration will be up to 5 years from study initiation, and annual data updates will be obtained from each data source. Annual data updates will continue until the earliest of (1) the target sample size being reached, or (2) 5 years elapsing since first EU availability.
4.5 Population:
There will be one study analysis population for the Spain arm of the study.
? Ospemifene Prescribed Population: any patient with a prescription of ospemifene (that is, all patients treated with ospemifene who are enrolled in the database). The use of ospemifene in any patients that are not postmenopausal (aged ?54 years) will be considered as off-label use.
Index Date: The index date (date of cohort entry) will be defined as the date of first ospemifene prescription
Inclusion Criteria: The Ospemifene Prescribed Population will include patients with at least one prescription or dispensation of ospemifene within the study period and at least 12 months of medical history (i.e., enrolment in the database or activity in the health system as a proxy for enrolment) prior to the index date.
Exclusion Criteria: There are no exclusion criteria.
Study Duration: The total study duration will be 5 years from the start of analysis. The maximum patient follow-up will be 5 years in the EU and 7 years in the US.
4.6 Variables:
Patient characteristics, medications, and select medical conditions at initial use of ospemifene. Exposure to ospemifene will be assumed to begin on the date of pharmacy dispensing or prescription, and continue to the date of the last prescription. The occurrence of specific indicators will be assessed if diagnosis or treatment occurs in the period extending from the 12 months preceding the first ospemifene to the date of the final prescription.
4.7 Data Source:
The data source for the Spain arm of the PASS is SIDIAP.
4.8 Study Size:
The Spain arm of the PASS will investigate off-label use of ospemifene: this is a descriptive study with an exploratory analysis (with no comparative component) of all patients with an ospemifene prescription, and therefore sample size calculations in this context can be interpreted as a forecast of patients using ospemifene.
4.9 Data Analysis:
Off-Label Use of Ospemifene
A descriptive analysis will be conducted examining the frequency of use of ospemifene that appears to be outside the indication in the EU label.
Patients who have been prescribed ospemifene will be categorised into three main groups. The first group will be designated ?On label? and patients will be included if there is clear evidence that the woman has a VVA diagnosis, is aged 54 years or over whilst receiving ospemifene prescription, and has no contraindications or off-label indicators. The second patient group will be designated ?Potentially on-label but lacking clear evidence of on-label indication?: all patients in this group will have neither contraindications nor other off-label indicators. The third and final patient group will be designated as ?Apparent off-label use?, and will have either contraindications, or have other off-label indicators.
The frequency distribution of patients by specific contraindication or other off-label indicator will be reported. In addition, an age distribution of patients with off-label indicators will be provided.
Post-Menopausal Women Who Are Not Candidates for Local Oestrogen Use (Restricted Conditions for Local Oestrogen Use)
A frequency distribution of patients prescribed ospemifene who have diagnosis or treatment for at least one of the following will be produced: history of melanoma, active treatment for breast cancer (including adjuvant therapy), history of breast cancer, history of endometrial cancer, porphyria, history of endometriosis and dexterity problems (Parkinson?s disease and/or history of stroke). Number and percentage of patients with conditions/indications which are both restricted for local oestrogen use and off-label/contraindicated for ospemifene will be highlighted.
4.10 Milestones:
The drug (ospemifene) is expected to be initially available in Italy, Spain and later in Germany. Ospemifene received approval from the US Food and Drug Administration (FDA) in 2013. Data collection will conducted annually after ospemifene is commercially available in the first European market. See Table A.1 (Appendices) for study milestones.

PREPARE (Plataforma para la preparación europea contra (re) epidemias emergentes) es una red financiada por la Comisión Europea para estudios de investigación clínica armonizados a gran escala sobre enfermedades infecciosas. El objetivo a largo plazo es establecer una red que esté preparada para responder rápidamente a cualquier brote de enfermedad infecciosa grave, proporcionando evidencia en tiempo real para el manejo clínico de los pacientes y para informar las respuestas de salud pública. Para obtener más información sobre PREPARACIÓN, visite nuestro sitio web (www.prepare-europe.eu).
Este estudio forma parte del estudio multicéntrico EuRopean de MAjor Infectious Disease Syndromes (MERMAIDS), que comprende el paquete de trabajo 3 (WP3) de la plataforma PREPARE.

Diseño del estudio
Estudio prospectivo, observacional.

Participantes del estudio
Adultos (? 18 años de edad) con sospecha de infección respiratoria aguda adquirida en la comunidad,
Grupo 1: atención primaria.
Grupo 2: hospitalizado.

Tamaño de muestra planificado
Pacientes de Atención Primaria (Grupo 1): n = 500
Pacientes hospitalizados (Grupo 2): n = 1.500

Periodo de estudio planificado
36 meses

Objetivo primario
Identificar determinantes relacionados con el hospedador y patógenos de la gravedad de las infecciones respiratorias agudas adquiridas en la comunidad (IRA) en adultos.

PREPARE (Plataforma para la preparación europea contra (re) epidemias emergentes) es una red financiada por la Comisión Europea para estudios de investigación clínica armonizados a gran escala sobre enfermedades infecciosas. El objetivo a largo plazo es establecer una red que esté preparada para responder rápidamente a cualquier brote de enfermedad infecciosa grave, proporcionando evidencia en tiempo real para el manejo clínico de los pacientes y para informar las respuestas de salud pública. Para obtener más información sobre PREPARACIÓN, visite nuestro sitio web (www.prepare-europe.eu).
Este estudio forma parte del estudio multicéntrico EuRopean de MAjor Infectious Disease Syndromes (MERMAIDS), que comprende el paquete de trabajo 3 (WP3) de la plataforma PREPARE.

Diseño del estudio
Estudio prospectivo, observacional.

Participantes del estudio
Adultos (? 18 años de edad) con sospecha de infección respiratoria aguda adquirida en la comunidad,
Grupo 1: atención primaria.
Grupo 2: hospitalizado.

Tamaño de muestra planificado
Pacientes de Atención Primaria (Grupo 1): n = 500
Pacientes hospitalizados (Grupo 2): n = 1.500

Periodo de estudio planificado
36 meses

Objetivo primario
Identificar determinantes relacionados con el hospedador y patógenos de la gravedad de las infecciones respiratorias agudas adquiridas en la comunidad (IRA) en adultos.

PREPARE (Plataforma para la preparación europea contra (re) epidemias emergentes) es una red financiada por la Comisión Europea para estudios de investigación clínica armonizados a gran escala sobre enfermedades infecciosas. El objetivo a largo plazo es establecer una red que esté preparada para responder rápidamente a cualquier brote de enfermedad infecciosa grave, proporcionando evidencia en tiempo real para el manejo clínico de los pacientes y para informar las respuestas de salud pública. Para obtener más información sobre PREPARACIÓN, visite nuestro sitio web (www.prepare-europe.eu).
Este estudio forma parte del estudio multicéntrico EuRopean de MAjor Infectious Disease Syndromes (MERMAIDS), que comprende el paquete de trabajo 3 (WP3) de la plataforma PREPARE.

Diseño del estudio
Estudio prospectivo, observacional.

Participantes del estudio
Adultos (? 18 años de edad) con sospecha de infección respiratoria aguda adquirida en la comunidad,
Grupo 1: atención primaria.
Grupo 2: hospitalizado.

Tamaño de muestra planificado
Pacientes de Atención Primaria (Grupo 1): n = 500
Pacientes hospitalizados (Grupo 2): n = 1.500

Periodo de estudio planificado
36 meses

Objetivo primario
Identificar determinantes relacionados con el hospedador y patógenos de la gravedad de las infecciones respiratorias agudas adquiridas en la comunidad (IRA) en adultos.

RATIONALE AND BACKGROUND:
Retinoic acid analogues comprise of a group of active substances known as the retinoids and are available as topical and oral preparations. Therapeutic indications include the treatment of severe acne (such as nodular or conglobate acne) resistant to adequate courses of standard therapy, hand eczema resistant to empirical treatment measures, and severe forms of psoriasis and other skin conditions.
Therapy with systemic retinoids is associated with teratogenicity. Therefore, women who are pregnant or are planning a pregnancy must not be prescribed retinoids. Strict prescription guidelines and a PPP comprising education material for patients, physicians, and pharmacists as well as strict prescription guidelines have been put in place but exposure during pregnancy still occurs. In January 2016, a Pharmacovigilance Risk Assessment Committee (PRAC) review noted that there are concerns about how well the requirements of the PPP are followed in clinical practice. In July 2016, the PRAC initiated an article 31 referral to assess the effectiveness of risk minimisation in relation to the PPP. After completion of the review in March 2018, the European Medicines Agency (EMA) confirmed that an update of measures of the PPP for the oral retinoids acitretin, alitretinoin and isotretinoin is needed. They, therefore, mandated the conduct of a DUS (category 1) to assess the effectiveness of these updated risk minimisation measures (RMMs). In June 2018, the decision to strengthen the recommendations for pregnancy prevention for oral retinoids was issued by the European Commission (EC).
RESERACH QUESTION AND OBJECTIVES:
The aim of the Drug Utilizacion Study (DUS) is to address the following research question:
Is there a difference in physicians’ prescribing and monitoring practice in the periods before and after the update of the pregnancy prevention programme (PPP) for the oral retinoids acitretin, alitretinoin, and isotretinoin when treating women of childbearing potential?
PRIMARY OBJECTIVE:
To evaluate the changes in the prescribing and monitoring practices following the update of the PPP in females of childbearing potential receiving prescriptions of the oral retinoids acitretin, alitretinoin, or isotretinoin by comparing the following key elements of the PPP between the pre- and the postimplementation period:
? Contraceptives* before, during, and after treatment with oral retinoids
? Time interval between prescription dates for oral retinoids during treatment episode
? Laboratory pregnancy tests ? where available – before, during, and after treatment with oral retinoids
* contraceptive methods that require prescription and which are, therefore, captured in the administrative databases
SECONDARY OBJECTIVES:
? To describe the patient profile during the pre-and the post-implementation period, with respect to:
o Patient age
o Indication for oral retinoids
? To describe the prescriber specialty during the pre-and the post-implementation period
? To describe the exposure characteristics during the pre-and the post-implementation period, with respect to:
o Active substance
o Dose
o Treatment duration
? To describe the incidence of pregnancies exposed to oral retinoids during the pre- and the post-implementation period
? To stratify the key elements of the PPP described in the primary objective by oral retinoid substance
? To describe trends in the physician?s prescribing and monitoring practice of oral retinoids with respect to measures of the PPP (contraceptive use and performance of pregnancy tests) over the entire duration the study
STUDY DESIGN:
This is a multicountry, multisource, observational cohort study in females of childbearing potential receiving oral retinoids (i.e., acitretin, alitretinoin and isotretinoin) using a pre-post design. This study will cover time periods before and after the implementation of the updated RMMs related to the PPP update. The study will be based on secondary use of data extracted from established longitudinal healthcare databases (claims, primary care database, national registries). The pre-implementation period consists of 2 distinct phases, a 2-year phase (07/2014 to 06/2016) prior to the start of the referral in July 2016 and a 2.5-year phase between the start of the referral and the distribution of EM for the updated PPP in Q4 2018. The post-implementation period captures the 2-year phase after the distribution of the EM (01/2019 to 12/2020).
POPULATION:
The study population will consist of females of childbearing potential (13-49 years of age, inclusive) receiving oral retinoids (i.e., acitretin, alitretinoin and isotretinoin) in the outpatient setting (at officebased practices and outpatient departments at hospitals), during the pre-defined periods identified from the selected data sources in the European target countries (i.e., France, Germany, Spain, and Sweden).
INCLUSION CRITERIA:
? Female gender
? Childbearing potential (13-49 years of age, inclusive)
? Received or prescribed at least one prescription of the oral retinoids acitretin, alitretinoin, or isotretinoin in either the pre-implementation or post-implementation period
EXCLUSION CRITERIA:
All females in the age group 13 to 49 years with available information that they are not of childbearing potential before initiation of oral retinoids (such as records of hysterectomy or sterilisation) will be excluded.
Data for the oral retinoids acitretin, alitretinoin, and isotretinoin will only be extracted from databases in target countries where the respective active substance has been granted market authorisation.
No further exclusion criteria will be applied.
VARIABLES:
The exposure is defined as one or more prescriptions of oral retinoids (i.e., acitretin, alitretinoin, orisotretinoin) during one of the study periods. The following variables will be considered (if available):
patient age, oral retinoid prescribing and monitoring practice such as indication, length of prescription, treatment duration, and prescriber speciality, as well as PPP-specific variables such as prescriptions of contraceptive and ? if available – laboratory pregnancy testing (before, during, and after treatment). In addition, information on exposed pregnancies and outcomes (if available) will be provided.
DATA SOURCES:
The following established longitudinal data sources will be utilised for data extraction:
Claims databases
? France: System National d’Information Inter-Régimes de l’Assurance Maladie (SNIIRAM) of the Système National des Données de Santé (SNDS)
? Germany: Collective of insurants from company health insurance funds Primary care database
? Spain: Sistema d?Informació per al Desenvolupament de l?Investigació en Atenció Primària (SIDIAP)
National health registers
? Sweden: national drug-, patient-, and birth registers
Study size:
All females of childbearing potential receiving oral retinoids (i.e. acitretin, alitretinoin, isotretinoin) available in pre-defined periods of the selected databases will be included in the analysis.
The number of females of childbearing potential receiving oral retinoids was checked for a 3-year
period (2015-2017) in Germany, Spain, and Sweden. The number of patients is approximately 3,700 in Germany, 4,800 in Spain, and 20,500 in Sweden.
In France, only the number of boxes that was reimbursed in France in total (without any restriction to age and gender) is available without receiving ethical approval for the study, the number of approximately 1,041,000 boxes in one year suggests that the number of female patients of childbearing potential receiving oral retinoids will be sufficient for analysis.
DATA ANALYSIS:
Given the study objectives, the analyses will mainly be descriptive and will be conducted by country and study time periods (both pre-implementation periods and post-implementation period). Some comparisons will be made especially between the different study time periods.
The analyses will be provided for the overall class of oral retinoids (acitretin, alitretinoin and isotretinoin) and for the single active substances.
Results for key variables will be presented over time where patient numbers permit to provide insights on continuous trends capturing pre- and post-implementation periods.
In addition, an interrupted time series (ITS) analysis will be considered in case the conditions for this analysis will be met.

Un ensayo clínico controlado, factorial, aleatorizado y grupal para evaluar si una intervención clínica centrada en la enfermedad continua (mejora de las habilidades de comunicación) y / o una intervención clínica centrada en la enfermedad (prueba rápida de proteína C reactiva) cambiará el consumo de antibióticos entre los pacientes con ALRTI dentro de las primeras seis semanas después de la consulta.

The HAPPY PATIENT project aims at reducing the inappropriate use and dispensing of antibiotics in the most common community-acquired infections (i.e., respiratory tract infections, urinary tract infections, dental infections) with a multifaceted intervention in health care facilities as suggested in point 4.2 of the EU guidelines for the prudent use of antimicrobials in human health. The multifaceted intervention will be carried out in five countries with a diverse pattern of antibiotic consumption: ES, FR, LT, PL and GR. We will follow a model which both promotes both stakeholder stewardship and is patient-centred. The critical focus will be on the most important interaction in determining usage of antibiotics: contact between patients and health professionals at different levels of the Health Care System. Hence, activities of HAPPY PATIENT will target patients, primary care professionals (general practitioners, nurses, and dentists), secondary care (out-of-hours services), nursing homes and community pharmacists.
We will follow the Audit Project Odense (APO) methodology developed in FP6 HAPPY AUDIT project. APO consists of an audit-based registration to perform a context analysis before the implementation of the multifaceted intervention, and then to perform an assessment of changes after the implementation of the multifaceted intervention. Based on the Normalization Process Theory for changing behaviour, the multifaceted intervention will include: a) peer feedback with reflexion and discussion, b) enhancement of communication skills in order to improve the communication process between the health professionals and the patients, c) patient information leaflets and posters, d) country-tailored information on antibiotic usage(incl. the “”antibiotic foot-print””).

Es disposa de poca informació de pacients amb infecció SARS-CoV-2 lleu i / o no diagnosticada. Aquests pacients solen contactar amb proveïdors d’atenció primària, ja sigui a la pràctica o per telèfon. Encara hi ha molta incertesa sobre qui desenvoluparà símptomes lleus o més greus en adquirir la infecció i qui corre el risc de complicacions greus. Per tant, realitzarem un estudi en atenció primària amb pacients amb infecció aguda de les vies respiratòries a 4-8 països europeus.

Objectiu: generar informació sobre la presentació i el control de pacients amb infecció aguda de les vies respiratòries agudes adquirides a la comunitat en atenció primària durant la pandèmia COVID-19, determinar la proporció d’aquests pacients infectats amb SARS-CoV-2 i factors de risc de complicació.

Disseny de l’estudi: estudi observacional prospectiu descriptiu amb seguiment durant 1 mes. Població: pacients amb un any i més, presentats en atenció primària, amb símptomes d’infecció respiratòria aguda adquirida a la comunitat durant la pandèmia COVID-19. S’avaluarà la proporció de pacients amb infecció per SARS-CoV-2 en pacients que presenten infecció respiratòria aguda en entorns d’atenció primària a diversos països europeus, amb descripció del curs de la malaltia (dies de malaltia, dies no productius, complicacions i la mort).

S’obtindrà una mostra nasal i faríngea a la visita inicial per avaluar presencia de SARS-CoV-2, altres virus i bactèries.

Justificación: Múltiples estudios han identificado factores relacionados con la evolución de la enfermedad COVID-19 desde su inicio en China. Actualmente España está entre los países con mayor número de infectados y muertos, lo que está generando datos útiles para su análisis y el futuro manejo de la enfermedad.
Objetivo: evaluar la asociación de factores sociodemográficos, clínicos y farmacológicos con la tasa de infección, la gravedad y el desenlace fatal del COVID-19.
Metodología: estudio observacional de cohortes de base poblacional en Cataluña. Análisis de variables sociodemográficas, comorbilidades y tratamientos para identificar factores de riesgo para la infección, mediante registro diagnóstico o PCR positiva para SARS-CoV-2, y su evolución (neumonía, ingreso, respiración asistida y muerte).