The Agency considers it requires a study to investigate exposure and use patterns of H2-receptor antagonists-containing medicinal products authorised in the European Union (EU).
The study should be carried out in at least five European countries with ideally equal spread across Western, Southern, Northern and Eastern countries and balanced representation of European healthcare services and setting with the following objectives:
1. To determine drug utilisation and prescription patterns of medicinal products containing H2-receptor antagonists (ATC codes: A02BA01 (cimetidine), A02BA02 (ranitidine), A02BA03 (famotidine), A02BA04 (nizatidine), A02BA06 (roxatidine), A02BA07 (ranitidine bismuth citrate), A02BA08 (lafutidine), A02BA51 (cimetidine, combinations) and A02BA53 (famotidine, combinations) by substance over a minimum period of five years (preferably more) including up to 2018 or more recent data. This study should give particular focus to:
a. Prescribing of medicinal products containing H2-receptor antagonists by incident and prevalent use by year, by indication (i.e. gastro-oesophageal reflux disease (GERD), gastric and duodenal ulcer, ulcer associated with H. pylori, Zollinger-Ellison syndrome), by age group, by gender, by dose, by formulation, by duration, by cumulative exposure and by country and data source;
b. To determine, in so far as is possible, comorbidity of renal impairment in patients using H2-receptor antagonist containing medicinal products.

Background
Clinical trials have shown an association between aromatase inhibitor (AI) use for the treatment of breast cancer and adverse musculoskeletal disease when compared with tamoxifen. This has not been investigated in routine clinical practice.

Hypothesis
In comparison to tamoxifen, AI use is associated with an increased incidence of carpal tunnel syndrome (CTS), tendinopathy, osteoarthritis and related procedures/surgery in post menopausal women with hormone receptor positive breast cancer.

Methodology
Cohort study design, using non identifiable SIDIAP OHDSI CDM mapped data in order to enable replication of the study internationally within the OHDSI network. All post-menopausal (defined >55 years) women with an incident diagnosis of breast cancer, with 6 months continous enrolment prior to diagnosis, and incident use of AI, tamoxifen, or both within 1 year of diagnosis. Those with a prevalent cancer, or outcome prior to breast cancer diagnosis are excluded. Incidence of fracture (vertebral and appendicular fractures) to be used as a positive control outcome.

Variables & Measurements
The date of exposure will be identified from the first drug exposure; outcomes defined as the first incident record of an outcome, each outcome assessed independently, identified using OMOP CDM ATLAS generated definitions.

Statistical Analysis
Propensity score adjustment to minimise confounding. Cumulative Incidence of outcome; cox proportional hazards modelling to estimate hazard ratios for each of the outcomes.

Expected results
Incidence of adverse musculoskeletal outcomes at a population level in Catalonia, with replication worldwide to enable international comparison.

Applicability
To counsel women at the beginning of treatment; consider earlier identification and surveillance during treatment.

Strengths & Limitations
The study is based upon drug dispensation rather than adherence, and only contains information from clinical services, leading to the potential to underreport an association. The study aims to increase generalisability through using OMOP CDM mapped data, to ensure the study can be replicated within the international OHDSI community.

Dietary N-nitrosodimethylamine (NDMA) has been shown to be carcinogenic in animals, however, evidence from population-based studies is inconlusive. The U.S. Food and Drug Administration has issued a statement on ranitidine because they may contain unacceptable levels of NDMA in 2019.
To date, there have been several studies regarding association between NDMA exposure and risk of cancer, however, real-world evidence of cancer risk in relation with ranitidine is scarce. We aim to evaluate the comparative risk of incident cancer in patients exposed to various H2 receptor antagonists (H2RAs).
We will conduct systematic, multinational study to estimate the relative risk of primary outcome (overall cancer except thyroid cancer) and secondary outcomes (overall cancer, 16 types of cancer, and cancer mortality) in ranitidine cohort. We will compare the target cohort with the comparator cohort for the hazards of outcome during the time-at-risk by applying a Cox proportional hazards model after propensity score adjustment.

Background
The use of hydrochlorothiazide (HCTZ) has been linked to skin cancer, and especially to non-melanoma skin cancer. However, the association has not been evaluated in a Mediterranean-origin population specifically, which has a phototype and sun exposure different from those of the Nordic populations.
Hypothesis
HCTZ exposure might be associated to an increased risk of skin cancer in non-Nordic European population.
Objectives
To assess the association between HCTZ exposure and risk of malignant melanoma (MM) and non-melanoma skin cancer (NMSC) in Spain using electronic health care data.
Methodology
Two independent case-control studies using data from BIFAP an SIDIAP datasets will be carried out.
Determinations and Statistical Analysis
Comparing MM and NMSC cases to disease-free population controls, the use and cumulative use of HCTZ will be assessed and odds ratios for the association will be estimated using conditional logistic regression.
Expected results and Applicability
The study will either confirm of disprove an association between HCTZ use and MM and NMSC in European people other than Nordic-origin.
Relevance and limitations
Knowledge of an increased skin cancer risk would allow prescribers to take appropriate measures, such as increased focus on UV protection or would even motivate regulatory actions on the use of HCTZ in the EU. Conversely, a disproved risk would reassure prescribers in the safety of the use of the drug.
The main limitation is the lack of direct measures of UV exposure history. However, there is no reason to suspect that HCTZ users will display markedly different sun exposure habits than the background population.

Antecedentes:
Se informa que los espacios de juego urbanos mejoran la salud de los niños, incluida la salud mental. A pesar de las sugerencias de esta asociación, hay poca evidencia disponible sobre el impacto de los espacios de juego (particularmente los no verdes) en la salud mental y del comportamiento infantil.

Hipótesis y objetivos:
Planteamos la hipótesis de que un mayor acceso a los espacios de juego residenciales se asocia con menores probabilidades de resultados de salud mental y conductual y que estas asociaciones serán más fuertes para las personas de características socioeconómicas marginadas.
Investigaremos las asociaciones entre la proximidad residencial a los espacios de juego (en general, verde y diversidad) y los resultados de salud mental y conductual diagnosticados. También exploraremos si estas asociaciones difieren según las características sociodemográficas a nivel individual y de área.

Métodos:
Probaremos la relación entre la exposición residencial a los espacios de juego y los resultados de los trastornos mentales y del comportamiento diagnosticados para 151110 niños que viven en la ciudad de Barcelona y que forman parte del conjunto de datos SIDIAP. Usaremos amortiguadores de área de servicio de 300 m alrededor de cada espacio de juego para estimar la proximidad residencial de los niños a los espacios de juego en general, los espacios verdes de juego y la diversidad del paisaje de juego en la zona de residencia del censo.
Usaremos modelos de regresión logística para investigar la asociación entre los espacios de juego y los resultados de salud. Además, para probar las diferencias en las relaciones por características sociodemográficas individuales y de nivel de área, probaremos términos de interacción para indicadores de espacios de juego y dos indicadores socioeconómicos (privación a nivel de área y etnia individual). Para aquellas características que muestren términos de interacción significativos, luego realizaremos modelos estratificados

Research question and objectives:
Co-primary:
– To estimate the incidence rates of adverse events of special interest (AESI) in the general population by calendar year and data source over the period 2017 to 2020.
– To estimate the incidence of pregnancy outcomes among pregnant women aged between 12 to 55 years old by calendar year and data source over the period 2017 to 2020.
– To estimate the weekly and monthly incidence rates of COVID-19 (overall and by severity level) in 2020 by data source.
– To estimate the monthly incidence rates of multisystem inflammatory syndrome in children (MIS-C) aged between 0 to 19 years old in 2020 by data source.
Secondary:
– To estimate the incidence rates of AESI in the general population by calendar year, sex, age group, and data source over the period 2017 to 2020.
– To estimate the incidence rates of AESI in the general population by month, sex, age group, and data source over the period 2017 to 2020.
– To estimate the incidence rates of multisystem inflammatory syndrome (MIS-C) in children in 2020 by month, sex, age group, and data source.
– To estimate the prevalence of high-risk medical conditions for developing severe COVID-19 by year and data source over the period 2017 to 2020.
– To estimate the incidence rates of AESI in the at-risk population for developing severe COVID-19 by calendar year, sex, age group, and data source over the period 2017 to 2020.

Study design: A retrospective multi-database dynamic cohort study, conducted during the years 2017 to 2020, including the period of SARS-CoV-2 circulation in Europe until the date of last data availability for each data source.

Population: The study population will include all individuals observed in one of the participating data sources for at least one day during the study period (01 January 2017 – last data availability) and who has at least 1 year of data availability before cohort entry, except for individuals with data available since birth.

Variables:
– Person-time: birth and death dates as well as periods of observation.
– Events: dates of medical and/or procedure and/or prescription/dispensing codes to identify AESI, pregnancy outcomes and at-risk medical conditions.

Rationale and background: DKP-TRAM is a pharmacologi¬cal fixed association with analgesic activity, which has been registered for treatment of acute pain in 2017 in several European Countries. In Spain and Italy, the product has been launched in January 2017 and March 2017, respectively. The safety and efficacy of DKP-TRAM (25 mg – 75 mg) combination has been extensively demonstrated in the clinical development program in more than 1800 patients, especially from randomized clinical trials (RCTs) in post-operative pain. However, there is limited evidence in the real-life use of the product in the primary care settings particularly in elderly patients where the use of the 75 mg dose (with no possibility of dose titration) of tramadol contained in the combination could be a source of safety concerns for the prescribers.
In the light of this background, the evaluation of the patterns of use and the safety profile of DKP-TRAM combination will be investigated through a real-world study involving an Italian and a Spanish database.
Furthermore, we will test the potential effect modification exerted by age (75 years or older vs. younger patient) or frailty (mild, moderate, severe) among elderly patients (aged 65 or older) on the risk of adverse events (AEs) likely due to DKP-TRAM.
Research question and objectives:
Primary objectives: To evaluate pattern of drug use (i.e. indication, dosage, and duration) of DKP-TRAM.

Secondary objectives:
? To assess the risk of AEs (nausea, vomiting, diarrhoea, vertigo, hallucinations, somnolence, and constipation) in incident users of DKP-TRAM vs. incident users of tramadol as monotherapy and fixed combination tramadol-paracetamol.
? To evaluate the effect modification exerted by age (75 or older vs. 74 or younger) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users.
? To evaluate the effect modification exerted by frailty (mild, moderate or severe) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users aged 65 years or older.

Background: The global burden of mental and behavioral health disorders has been increasing in the last 30 years. These disorders cause premature mortality and pose an important public health burden. As the world population becomes more urbanized, the metropolitan environment continues to result in negative physical and mental health effects; however, green spaces have been shown to act as a buffer to these negative health effects. Although the relationship between mental health and green spaces has been investigated in previous studies, there are still gaps, especially with regards to the relationship between green spaces and specific mental and behavioral disorders.
Objective: To determine the association between green space (NDVI, percentage of green spaces) and the risk of developing depression, anxiety, stress, OCD and eating disorders in adults in Catalonia.
Methods: We will conduct a cohort study using data from the Information System for Research in Primary Care (SIDIAP). We will include all persons registered in the SIDIAP who are aged ?18 years between January 1, 2009 and December 31, 2018. The exposure of interest will be the availability of green spaces (measured using NDVI and the percentage of green space at the census tract level). Outcomes will be captured through diagnostic codes (ICD-10) of each mental and behavioral disorder. To evaluate the association between green spaces and the risk of each specific mental and behavioral disorder, cox proportional hazard models will be fitted to estimate cause specific hazard ratios (HR) and 95% confidence intervals (CIs).

The global pandemic of COVID-19 has resulted in over 50 million reported cases and over 1.2 million deaths globally. Meanwhile, hundreds of clinical trials of vaccines are ongoing and some of them show clinical efficacy. While planning for the large-scale immunization program, it is important to understand the potential adverse events after vaccination or viral infections. Electronic health records have been increasingly used in safety study, including SIDIAP. The ability to and the reliability of capturing the adverse events using suitable phenotyping algorithms in such databases is the foundation in conducting these studies. We will firstly identify the phenotyping algorithms of the AESI used in other studies, or develop the phenotypes if no existing one is found. Then we will evaluate the performance of these phenotypes using the diagnostic and evaluation tool that had been previously developed. The second objective is to estimate the background incidence rates (IR) of the AESI among the general population from year 2006 to 2019. Individuals who were observed for at least 365 days in the dataset during the study period will be included. The numerator of the incidence rate will be the total number of incident cases in a given year, and the denominator will be person-time at risk in each year. We will also estimate the IR among patients who were diagnosed or received a positive test for COVID-19 (after February 2020) or seasonal influenza. We will apply different algorithms in identifying both the exposures and the outcomes. We will also conduct a self-control case series analysis to explore the association between developing the AESI and COVID-19 or influenza infections.

Approximately 10-20% of COVID-19 positive patients, many of whom are older or have co-morbidities, suffer from pneumonia and acute respiratory distress syndrome (ARDS), requiring hospitalization and ventilatory support. It has been suggested that this population is also at higher risk of inflammatory immune system disorders. As a result, current treatment recommendations are to combine anti-viral therapy with immunosuppressive or immunomodulatory drugs to mitigate these immunologic complications, reducing COVID-19 associated morbidity and mortality. While the search for appropriate anti-viral therapy is ongoing, there have been some positive results with respect to systemic glucocorticoid use, such as dexamethasone, which has been associated with reduced mortality in ventilated patients and those on supplemental oxygen therapy. This has mobilised efforts to repurpose some of these steroids for the treatment of severe COVID-19 cases. That said, a lot of information on steroid use in COVID-19 patients is currently missing. Treatment type, dosage, timing of administration, as well as identification of patient risk groups that will benefit most from the treatments, is inadequately explored. To partially address these research gaps, this protocol describes a non-comparative study to explore patterns of systemic glucocorticoid use and administration in patients with either a first confirmed diagnosis for COVID-19 (diagCOVID-19) or a first positive PCR test for SARS-CoV-2 (labCOVID-19) using healthcare databases from seven European countries. The aim of this study is to describe patterns of systemic glucocorticoid use, as well as the risks of adverse events associated with these medications, in diagCOVID-19 or labCOVID-19 patients across seven European countries in ambulatory and hospital inpatient care settings.