Dan Ouchi Vernet

RATIONAL AND BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic, multisystemic, autoimmune, systemic rheumatic disease of clinical and biologic heterogeneity. Given the individual variability in SLE manifestations, there is no single treatment paradigm. A tailored, multidisciplinary strategy is required which needs to be adjusted to patients’ individual clinical manifestations. Anifrolumab, a human monoclonal antibody that binds to subunit 1 of the type 1 interferon receptor (IFNAR1), was developed based on the evidence supporting the role of type 1 interferon pathway in SLE. Anifrolumab was approved via a centralised procedure in the European Union (EU) on 14 February 2022. It is indicated as an add-on therapy for the treatment of adult patients with moderate to severe, active autoantibody SLE, despite standard therapy (EMEA/H/C/004975/0000). As part of the original marketing authorisation application to the European Medicines Agency, AstraZeneca included a proposal to conduct a non-interventional multi-country post-authorisation safety study to characterise the risk of malignancies and serious infections among real-world users of anifrolumab.
RESEARCH QUESTION AND OBJECTIVES: The main research question is to evaluate the risk of malignancies and serious infections among moderate/severe SLE patients who receive anifrolumab compared with a comparable population of moderate/severe SLE patients on standard of care (SOC) who do not initiate anifrolumab.
– Primary objectives
The following objectives pertain to the malignancy outcomes:
1) To estimate the incidence of new malignancies (as a composite outcome) in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
2) To compare hazard rates of new malignancies (as a composite outcome) in moderate/severe SLE patients initiating anifrolumab versus comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
The following objectives pertain to the serious infection outcomes:
3) To estimate the incidence of the first occurrence of a serious infection (as a composite outcome) in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
4) To compare hazard rates of the first occurrence of a serious infection (as a composite outcome) in moderate/severe SLE patients initiating anifrolumab versus comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
– Secondary objectives
The following objective pertain to the malignancy and serious infection outcome cohorts:
5) To describe the demographic and clinical characteristics of patients in each study cohort (malignancy cohort and serious infection cohort) at index date, by exposure status (exposed to anifrolumab vs. exposed to SLE SOC).
The following objectives pertain to the malignancy outcomes:
6) To estimate the incidence of new pre-specified malignancy sub-types (separately) in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
7) To compare hazard rates of new pre-specified malignancy sub-types (separately) in moderate/severe SLE patients initiating anifrolumab versus comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
The following objectives pertain to the serious infection outcomes:
8) To estimate the incidence of serious infection components – infections leading to hospitalisation, infections requiring treatment with intravenous antimicrobials, or infections related to death – in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
9) To estimate the incidence of the first occurrence of opportunistic serious infections, other serious infections, pneumonia (overall), fatal and non-fatal pneumonia (separately) in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
10) To compare hazard rates of the first occurrence of opportunistic serious infections, other serious infections, pneumonia (overall), fatal and non-fatal pneumonia (separately) in moderate/severe SLE patients initiating anifrolumab versus comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC), when feasible (i.e., if sample size allows).
Exploratory objectives
The following objectives pertain to the serious infection outcomes:
11) To estimate the incidence of recurrent infections leading to hospitalisation, in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC).
12) To compare the hazard rates of recurrent infections leading to hospitalisation in moderate/severe SLE patients initiating anifrolumab and in comparable moderate/severe SLE patients who do not initiate anifrolumab (exposed to SLE SOC), when feasible.
STUDY DESIGN: This long-term safety study is a cohort study based on secondary use of data from Denmark, France, Germany, and Spain. The study will start after anifrolumab market launch dates in each of these countries. For malignancies, the study period will end on the 31st of May 2029 and for serious infections it will end on the 31st of May 2025.
This study is based on a prevalent new-user design, i.e., adult patients with a SLE diagnosis, previous exposure to SLE SOC (indicated for moderate to severe SLE), uncontrolled SLE and initiating anifrolumab (exposed to anifrolumab) will be compared with a comparable group of patients who do not initiate anifrolumab (exposed to SLE SOC). Time-based exposure sets will be created to identify comparative study cohorts. Exposure sets will be defined within a time interval (+/- 45 days, [wider time intervals may be considered if matches cannot be obtained using this time window]) of anifrolumab initiation where all comparator members within each set match the anifrolumab exposed patient according to time since first SLE SOC prescription. Additionally, to increase comparability, comparators will be selected taking into account SLE disease activity (uncontrolled SLE despite SOC), disease severity and matched on propensity scores (PS).
Two cohorts will be constructed for the outcomes of interest (a malignancies cohort – for evaluating new malignancies as a composite outcome and for malignancies’ sub-types; and a serious infections cohort – for evaluating serious infections outcomes), considering outcome-specific inclusion and exclusion criteria. In the main analysis, on-treatment definition of exposure will be considered: patients will be considered at risk while exposed to the first anifrolumab treatment (or the SOC treatment for the exposed to SLE SOC group). For the analysis of malignancy outcomes, follow-up will start after a 12-months latency period after the index date and an additional 12-months period at risk (off-drug) will be considered to capture outcomes that might occur after drug cessation.
EXPOSURE VARIABLES: Patients exposed to anifrolumab will be defined by the initiation of anifrolumab (anatomical therapeutic chemical code L04AA51).
SLE SOC patients will be defined by the use of drugs indicated for moderate to severe SLE (in addition to antimalarials and/or low dose corticosteroids): medium to high dose corticosteroids, immunosuppressants (synthetic or biologics [except anifrolumab]), plasmapheresis or intravenous immunoglobulins.
OUTCOME VARIABLES
– Primary outcomes
Malignancies will be defined as the first coded diagnosis for haematological malignancies and solid tumours available in the data sources.
Serious infection will be defined as an infection leading to hospitalisation, use of intravenous antimicrobials or an infection-related death, operationalised as:
Infections leading to hospitalisation: a) infection diagnosis as part of a hospitalisation episode or b) infection diagnosis in primary or secondary care settings up to 7 days before hospitalisation.
• Prescription/administration of intravenous antimicrobials.
• Infection-related death: recorded diagnosis of infection in primary or secondary care settings with record of death within the subsequent month.
– Secondary outcomes
Specific types of malignancies: haematologic, solid and skin malignancies.
Serious infection components: infection leading to hospitalisation, infection requiring treatment with IV antimicrobials and infection-related death.
Serious infection types grouped as opportunistic serious infections, other serious infections, pneumonia (overall), fatal and non-fatal pneumonia (separately)
– Exploratory outcomes
All episodes of infections leading to hospitalisation.
OTHER VARIABLES: The following variables will be used to describe the cohorts’ characteristics and to control for confounding: demographics, lifestyle characteristics, SLE disease history (including measures of disease severity and activity), medical history and comorbidities, healthcare resource utilisation and other risk factors specific for malignancies and/or serious infections.
DATA SOURCES: This study will use secondary data from multiple countries. The final list of data sources is based on a feasibility assessment conducted between June 2022 and January 2023. All data elements for this study will be collected from information routinely recorded in the regional and national data sources of:
– Denmark (Danish National Registries)
– France (National Health Data System)
– Germany (Statutory Health Insurance Claims)
– Spain (Information System for the Development of Primary Care Research)
STUDY SIZE: Study size estimations were carried out for the primary outcomes (serious infections and malignancies) at the meta-analysis level varying four parameters – hazard ratio, standard deviation (SD) of hazard ratio, background estimate of the primary outcome, and matching ratios of exposed:non-exposed patients. Simulations were run to calculate expected power to detect a pre-specified hazard ratio (HR) given an overall sample size; and to get exact sample size estimates to achieve 80% power to detect the pre-specified HR. Three specifications of HR threshold were considered, 1.5, 1.8, and 2.0, along with two pre-specified SD (0.1 and 0.2) of HR to get an effect-distribution in lognormal space within which the true HR lies. The background estimate of incidence of serious infections was varied from 9.6 to 39.8 per 1000 person-years, while the background estimate of incidence of malignancies incidence was varied from 5.26 to 6.31 per 1000 person-years. Matching ratios of exposed to non-exposed patients were specified as 1:1 and 1:3. Achieved power was computed for sample sizes ranging from a total of 500 anifrolumab exposed patients across all study countries to 5000 anifrolumab exposed across all study countries.
Approximately 1,312 anifrolumab exposed patients across all study countries would be necessary to achieve 80% power to detect a true HR of 1.5 (geometric mean of 0.405 in lognormal space) from an effect distribution with 0.2 SD (geometric coefficient of variation of 0.132 in lognormal space) for serious infections outcome. This assumes a matching ratio of 1:3, and background IRs of serious infection of 39.8 per 1000 person years.
Approximately 3,195 anifrolumab exposed patients across all study countries would be necessary to achieve 80% power to detect a true HR of 1.5 (geometric mean of 0.405 in lognormal space) from an effect distribution with 0.2 SD (geometric coefficient of variation of 0.132 in lognormal space) for malignancy outcome. This assumes a matching ratio of 1:3, and background IRs of malignancies of 6.31 per 1000 person years.
STATISTICAL ANALYSES: The data analysis for all the study objectives will be performed separately for each data source and using appropriate study sub-cohorts. In this study, PS adjustment will be performed separately in each data source to control for confounding using a prevalent new user design. First, time-based exposure sets will be defined based on duration of SLE SOC use: for each exposed patient, the time-based exposure set will include all unexposed patients with a similar duration of SLE SOC use as the exposed when they become exposed to anifrolumab. A single time-conditional propensity score model will be fit using all the exposure sets. This model will then be used to compute a time-conditional propensity score for all patients (exposed and unexposed) in each time-based exposure set. Each exposed patient will then be matched with up to three unexposed patients from his time-based exposure set by selecting those patients with the closest time-conditional propensity score. Covariate balance after matching will be assessed by calculating the absolute standardised differences for each variable between the study sub-cohorts.

Since the advent of biologic agents targeting key proinflammatory pathways, the treatment of chronic inflammatory and autoimmune diseases has substantially changed. Rheumatoid arthritis and psoriasis are two of the most common conditions for which these agents are administered. Patients taking biologics are more prone to mild infections; however, since most trials conducted have been of short duration, long-term follow-up of these individuals is necessary. Their association with serious infections has not yet been thoroughly analyzed.
In response to the need for further investigation into the long-term effects of biologic therapies, we propose a cohort study of patients with rheumatoid arthritis and/or psoriasis, comparing those exposed to biologic drugs with those who have not been exposed. We aim to analyze the association with potentially severe infections, including influenza, sepsis, pneumonia, and COVID-19.
This study aims to evaluate the association between biologic exposure and the incidence of serious infections, including COVID-19, influenza, pneumonia, and/or septicaemia, in patients diagnosed with rheumatoid arthritis and/or psoriasis in the general population of Catalonia.
Specific objectives:
To describe the sociodemographic and clinical characteristics of patients with rheumatoid arthritis and/or psoriasis, including their comorbidities, pharmacological treatments in use, and the prevalence of serious infections in this population.
To evaluate the association between different biologics and the incidence of life-threating infections in patients diagnosed with rheumatoid arthritis and/or psoriasis.
To evaluate the association between the duration of biologic exposure and the incidence of these infections in the same patient population.
To assess the impact of recent biologic exposure (within the last two months) on the incidence of these infections in the same patient population.
To evaluate the impact of comorbidities on the associations between biologic therapy and the incidence of infections in the same patient population.
To determine the influence of concurrent immunosuppressive therapies on biologic exposure and their relationship with the incidence of infections in the same patient population.
Design: Population-based cohort study.
Study period: A ten-years period, from January 1, 2014, to June 2024.
Population: Adult patients diagnosed with rheumatoid arthritis and/or psoriasis treated with biologic and non-biologic therapies will be identified in the primary healthcare records in Catalonia (ECAP), and they will be categorized into different cohorts based on their prior exposure to biologic treatments.
Data analysis:
The study population will be described overall and stratified by exposure status (exposed vs. unexposed individuals). Quantitative variables will be summarized using means with standard deviations (SD) or medians with interquartile ranges (IQR), depending on the distribution of the variable. Categorical variables will be presented as absolute and relative frequencies. Bivariate comparisons between groups will be conducted using Student’s t-tests, Wilcoxon rank-sum tests, or Chi-square tests, as appropriate.
For the primary outcome, marginal structural models (MSMs) will be employed to estimate the risk of treatment exposure while addressing confounding. Inverse probability of treatment weights (IPTWs) will be derived from propensity scores calculated using age, sex, socioeconomic deprivation score, previous life-threatening infections, and other relevant clinical factors. If necessary, weights will be truncated at the 1st percentile to stabilize estimates. Covariate balance before and after weighting will be evaluated using the standardized mean difference (SMD). Variables with SMD > 0.1 after weighting will be included in the MSM as additional covariates to achieve double robustness.
IPTWs will then be applied in logistic regression models to estimate risk ratios (RRs) with 95% confidence intervals (CIs), using robust standard errors (SEs) to account for variability. Statistical significance will be determined using the Wald test at a 0.05 level. When assessing the association between prior biologic exposure and severity outcomes, patients will be assigned to the worst outcome observed (all-cause death > hospitalization > disease presence) to ensure a mutually exclusive classification.
All analyses will be performed using R software (v4.2 or above).

Objetivos: Evaluar la efectividad clínica de 2 pautas antibióticas de fosfomicina: 3 g de fosfomicina trometamol monodosis y 3 g de fosfomicina trometamol una vez al día, 2 días.
Diseño: Estudio observacional con medicamentos (Active comparator New user design that emulates a target trial).
Ámbito de estudio: pacientes de la base de datos de un proyecto previo ITUCAT, que contiene información registrada de pacientes de la base de datos SIDIAP (Sistema de Información para el Desarrollo de la Investigación en Atención Primaria) entre los años 2012-2021.
Población de estudio: Todas las mujeres = de 18 años no embarazadas con diagnóstico de infección urinaria baja no complicada (IUBNC) o cistitis, que hayan iniciado un tratamiento antibiótico en monoterapia con fosfomicina en el período comprendido del estudio y que hayan sido atendidas en alguno de los centros sanitarios del instituto catalán de la salud (ICS) y con registro en la base de datos de SIDIAP.
Variables: necesidad de un segundo antibiótico a los 7 días, a los 14 días y a los 28 días, incidencia de pielonefritis durante los 28 días posteriores a la fecha índice, días hasta la recepción de un segundo antibiótico tras la fecha índice.
Análisis estadístico: Todos los análisis se realizarán mediante el software estadístico R (versión 4.3.1)
Resultados esperados, aplicabilidad, relevancia y limitaciones:
En base a resultados previos se espera encontrar que la fosfomicina 3 g monodosis sea inferior al tratamiento de dos dosis en IUBNC en mujeres adultas. Ante la ausencia de información entre las diferentes pautes antibióticas que se utilizan en Cataluña, este estudio permitirá aportar información de cuál es el tratamiento óptimo para el manejo de las IUBNC. Asimismo, se realizará un target trial emulation que permitirá reducir al máximo los sesgos inherentes a los estudios observacionales. El hecho de que tengamos un número de muestra grande permitirá analizar la efectividad clínica de ambos antibióticos en función de diferentes covariables. Asimismo, este estudio se comparará con el estudio SCOUT para comparar un ensayo clínico con un estudio similar utilizando real world data.
Sin embargo, no debemos obviar que se trata de un estudio observacional y aun cuando, se trata de minimizar al máximo los sesgos, pueden existir debido a que hay variables confusoras que no se conocen y no se pueden tener en consideración en el análisis.
Los datos necesarios para la realización del proyecto se realizarán mediante la reutilización de la base de datos del proyecto ITUCAT. Este proyecto contiene datos de la base de datos SIDIAP (de la historia clínica del ECAP, y del Conjunto Mínimo Básico de Datos (CMBD) de altas hospitalarias (CMBD-AH y de urgencias (CMBD-URG) y datos del registro de medicamentos de dispensación hospitalaria (MHDA).

La insuficiència cardíaca (IC) es classifica habitualment segons la fracció d’ejecció del ventricle esquerre (FEVE), de manera que es diferencien tres fenotips: IC amb FEVE reduïda (ICFEr), quan és = 40%, IC amb FEVE lleugerament reduïda o intermèdia (ICFEmr), quan està entre 41-49%, i IC amb FEVE conservada (ICFEc), si FEVE = 50%. També és habitual utilitzar la classificació funcional de la Nova York Heart Association (NYHA) per a descriure el grau d’IC, basada en la gravetat dels símptomes que presenta el pacient.
L’objectiu del tractament de la IC és reduir la mortalitat, reduir el risc d’hospitalitzacions per descompensació de la malaltia i millorar la simptomatologia. El tractament farmacològic recomanat segons l’evidència científica varia en funció del fenotip de IC.
L’objectiu d’aquest estudi és descriure les característiques clíniques i sociodemogràfiques de les persones diagnosticades de IC i els tractaments farmacològics que s’utilitzen per al maneig de la malaltia.
Recentment hem dut a terme aquest estudi a Catalunya, mitjançant la base de dades de SIDIAP. El nostre objectiu és replicar el mateix estudi amb dades nacionals procedents de BIFAP per a poder comparar els resultats.

La malaltia pulmonar obstructiva crònica (MPOC) és una patologia respiratòria comuna i prevenible, caracteritzada per una obstrucció progressiva i irreversible del flux aeri. El tabaquisme és el principal factor de risc, tot i que hi ha influències ambientals i genètiques. Els símptomes predominants inclouen la dispnea i la tos crònica, i sovint es produeixen exacerbacions que empitjoren la qualitat de vida del pacient. A Catalunya, la prevalença estimada de la MPOC és del 17,3%, la més alta d’Espanya, amb una mortalitat de 37,4 per 100.000 habitants. El diagnòstic i tractament es basa en la classificació GOLD, segons la funció pulmonar (FEV1), i en una estratificació per símptomes i antecedents d’exacerbacions. El tractament farmacològic inclou broncodilatadors de llarga durada (LABA, LAMA) i, en certs casos, corticoides inhalats (CI), especialment en pacients amb eosinofília elevada.
L’objectiu general de l’estudi és caracteritzar l’evolució dels patrons de tractament farmacològics inhalats i els resultats en salut en dues cohorts de pacients amb MPOC (incidents i prevalents) en el sistema sanitari català durant els darrers anys (2019-2024).
Metodologia: Estudi observacional de cohorts de base poblacional. La cohort 1 estarà formada per aquelles persones amb nou diagnòstic de MPOC durant el període d’estudi (diagnòstics incidents). La cohort 2 estarà formada per aquelles persones amb diagnòstic de MPOC actiu en diferents talls transversals durant el període d’estudi (diagnòstics incidents i prevalents).
Anàlisi estadística: El tractament dels registres de medicaments es durà a terme segons el protocol desenvolupat pel grup, basat en l’algorisme smooth.
Els objectius d’estudi s’analitzaran per separat a les dues cohorts. Les anàlisi segons els objectius específics, seran:
1. Descriptiva de les característiques basals en el moment d’entrada a la cohort:
a. Variables categòriques: Freqüències absolutes i relatives (percentatges), comparades entre cohorts amb test ?² o Fisher exacte (si n < 5 per cel·la). b. Variables contínues: Mitjana ± desviació estàndard (distribució normal) o mediana [RIQ] (distribució no normal), comparades amb t-test o Wilcoxon-Mann-Whitney. c. Temps zero: Cohort 1 (data inici tractament), Cohort 2 (01/01/2019). 2. Trajectòries de tractament broncodilatador (Cohort 1): a. Anàlisi longitudinal: Descripció de canvis (inici, monoteràpia, biteràpia, triple teràpia) i discontinuacions mitjançant: b. Diagrames de flux (transicions entre estadis de tractament). 3. Tractament broncodilatador en talls transversals (Cohort 2) a. Prevalences puntuals: Percentatge de pacients en cada estadi de tractament (LABA, LAMA, CI o combinacions d'aquestes) cada 6 mesos (gener/juliol 2019-2024). b. Comparació temporal: Tendències avaluades amb models logístics multinivell (efecte aleatori per pacient) o Cochran-Armitage (tendències lineals). 4. Anàlisi d’aguditzacions/exacerbacions de la MPOC: a. Taxes d’incidència: i. Hospitalitzacions: Nombre d’events/persona-temps (IC95% Poisson). ii. Aguditzacions en AP: Models Poisson/Negative Binomial per sobre-dispersió, ajustats per edat/sex/comorbiditats. b. Comparació entre cohorts: Raons de taxes ajustades (IRR) amb regressió multivariable. 5. Anàlisi de l’impacte de la pandèmia COVID-19 en els pacients de la cohort 2 respecte a canvis de tractament i a morbi-mortalitat. a. Canvis en tractament: Comparació pre/post-pandèmia (març 2020) amb test de McNemar (parellat) i GEE (per a dades longitudinals). b. Morbi-Mortalitat: Comparació pre/post pandèmia. Aplicabilitat i utilitat pràctica dels resultats de l’estudi: Els resultats que s’obtinguin d’aquest estudi seran utilitzats per l’elaboració de futures pautes d’harmonització farmacoterapèutica i/o esquemes de tractament de la MPOC, pel qual seran d’aplicació directa a l’atenció primària.

Aquest estudi preten classificar els pacients de MPOC en dues classificacions: una segons la gravetat (GOLD) i una altra segons trets clínics i biològics (Trets Tractables), per personalitzar millor el tractament. Un cop fetes les classificacions es preten explorar, tractaments administrats i la incidència de noves exacerbacions i mortalitat. Les dades provenen de la base SIDIAP, i tambe´ es busca identificar prescripcions inadequades i desigualtats en l’atencio sanitària.

Rationale and Background: This study will be conducted following the initial marketing authorization of ZEPOSIA® (ozanimod) for the treatment of multiple sclerosis (MS) to observe incidence rates of specific adverse events of interest (AEIs). The AEIs in this Post-Authorisation Safety Study (PASS) were selected based on the mechanism of action of ozanimod (sphingosine 1 phosphate [S1P] receptor modulation), ozanimod nonclinical data, possible class effects and safety issues identified with currently marketed S1P receptor modulator compounds in the MS indication based on AEIs observed in the clinical trials for ozanimod (marketed as ZEPOSIA®).
Research Question and Objectives:
Research question: What are the rates of AEIs in a real-world population of patients with relapsing remitting multiple sclerosis (RRMS) receiving newly marketed product ZEPOSIA® (ozanimod), an oral S1P receptor modulator (exposed) compared to the rates of these events in 2 populations of patients (not exposed to ozanimod) with RRMS who have received treatment with other S1P-receptor modulators or non-S1P receptor disease-modifying treatments (DMTs)?
Primary Objectives: The primary objectives of this study will be carried out through multinational distributed data sources that include secondary databases, such as Optum Research Database (ORD) and Clinical Practice Research Datalink (CPRD) and RRMS cohort and registry data sources in the United Kingdom (UK) and Europe:
•To describe the incidence rate and hazard ratio of major adverse cardiovascular events (MACE) within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used to treat RRMS.
•To describe the incidence rate and hazard ratio of serious opportunistic infections (SOI) within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used in the treatment of RRMS.
•To describe the incidence rate and hazard ratio of serious acute liver injury (SALI) without predisposing risk factors within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used in the treatment of RRMS.
•To describe the incidence rate and hazard ratio of macular edema within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used to treat RRMS.
•To describe the incidence rate and hazard ratio of malignancies within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used to treat RRMS.
•To describe the incidence of acute non-fatal myocardial infarction during exposure to ozanimod and exposure to other therapies used to treat RRMS.
•To describe the incidence of acute non-fatal stroke during exposure to ozanimod and exposure to other therapies used to treat RRMS.
•To describe the incidence of cardiovascular (CV) mortality during exposure to ozanimod and exposure to other therapies used to treat RRMS.
•To evaluate the study outcomes among patients 55 years or older compared to patients younger than 55 years.
Secondary Objectives:
•To describe the incidence of MACE during exposure to ozanimod and exposure to other therapies used to treat RRMS in intervals of time since initiation (ie, < 365 days and = 365 days). •To describe the incidence of symptomatic bradycardia during exposure to ozanimod and exposure to other therapies used to treat RRMS. •To describe the incidence of progressive multifocal leukoencephalopathy (PML) during exposure to ozanimod and exposure to other therapies used to treat RRMS. •To describe the incidence of SALI with and without predisposing factors within the person-time of exposure to ozanimod and the person-time of exposure to other therapies used in the treatment of RRMS. •To describe the incidence rate of posterior reversible encephalopathy syndrome (PRES) during exposure to ozanimod and exposure compared to other therapies used to treat RRMS. Study Design: This is a long-term observational study including patients exposed to ozanimod or other medications used to treat RRMS. The study will use existing multinational distributed data sources, such as administrative healthcare data, electronic health records, and potentially disease registries, which will not be collected primarily for this research but do reflect care in usual clinical practice. Exposure in the automated datasets will be based on prescription or dispensing data. As in usual practice, patients may switch between study drugs, and thus the analysis will be episode-of-use level, rather than patient level. Propensity scores (PS) based on relevant baseline demographics, clinical characteristics, and number of prior treatments at the start of each new treatment episode will be used to adjust for potential confounding in comparative analyses. The primary endpoints of interest are MACE (composite and the individual components of MACE), SOI, and SALI, macular edema, and malignancy. The study will estimate the incidence rates of these events in one exposed (ozanimod), and two comparator cohorts, defined by selected DMTs for MS. Hazard ratios will be considered the main measure of effect. A cohort design will allow direct estimation of the incidence rates, rate differences, and relative risk or hazard ratios of multiple outcomes of interest among new users of ozanimod compared with new users of other DMTs. A cohort study design will also allow accurate chronologic confounder assessment and assessment of the outcomes at multiple time points. The covariate information will be assessed during the time preceding treatment initiation and will include all relevant demographic and clinical characteristics available for each patient. Population(s): The study population will include men and women at least 18 years old who have a diagnosis of MS and are new users of (“initiate”) treatment with one of three cohort-defining treatments. Patients will be grouped into the following cohorts: •Exposed: Starting ozanimod •Non-exposed: Starting another S1P receptor modulator •Non-exposed: Starting a DMT other than an S1P receptor modulator Data Sources: The study cohorts include multinational distributed data sources that will be drawn from electronic databases from health systems in which ozanimod is launched and in countries where reimbursement status is anticipated to be granted or has been granted. The primary sources of data will include the: Optum (USA), Clinical Practice Research Datalink Aurum (UK), GEPARD (Germany), PHARMO (The Netherlands, to be included in the amendment) and SIDIAP (Catalunya, Spain, to be included in the amendment). Study Size: The size of the study cohorts will be determined by the uptake of ozanimod and comparator drugs in the countries and populations included in the data sources during the study period, and the amount of person-time each patient will contribute will depend on how long they remain on specific treatments. Data Analysis: When ozanimod-treated patients reach 1,000 patient-years in at least one data source, the study will conduct the PS-based analyses for the primary objectives in that data source as described below. Selective removal of observations, known as “trimming,” will be implemented at both ends of the PS weight range. At the low end of the range, all patient episodes with a PS weight below the 2.5 percentile value of the distribution of scores in the exposed group (ie, ozanimod) will be excluded. At the upper end of the range, we will exclude all patients, exposed and unexposed to ozanimod, with PS weights greater than the 97.5 percentile.

Aquest protocol correspon a un dels “case studies” que es porten a terme dins del “TARGET EU – ROC19: Comparative effectiveness and safety studies using the target trial emulation (TTE) and estimand frameworks”, SIDIAP 640 (reunió Comitè Científic abril 2025), que tenia com a objectiu estudiar la viabilitat de portar estudis de TTE a diferents bases de dades i seleccionar-ne vàries per portar a terme els estudis proposats. Ens han seleccionat per portar a terme el “CASE STUDY 4: Rivaroxaban and risk of major gastrointestinal bleeding in elderly patients with non-valvular atrial fibrillation” que es descriurà a continuació. L’estudi es farà amb el CDM de ConcePTION i reutilitzarem la instància de 31/12/2024.
Background: Non-valvular Atrial fibrillation (NVAF) is a common arrhythmia that presents a significant morbidity and mortality risk. Current evidence suggests important differences in bleeding risk between DOACs that may be particularly relevant in high-risk population, such as the elderly, who tend to be underrepresented in RCTs. The purpose of this study is to compare the safety of apixaban versus rivaroxaban in older adults with NVAF, with a particular focus on major gastrointestinal bleeding.
Objectives: The primary objective is to estimate the effect of initiating rivaroxaban versus apixaban on time to a first major gastrointestinal bleeding event. Methods: We will conduct an active comparator new-user cohort study using linked electronic health records from Denmark (Danish national registers) and Spain (SIDIAP). Eligible individuals are adults (=75 years) who initiated rivaroxaban or apixaban between 2012 (2014 en cas de SIDIAP) and 2023 (o 2024 segons instància actual, a discutir). In the primary analysis, a while on treatment strategy is used for treatment-related intercurrent events (discontinuation, switching). Inverse probability of treatment weighting (IPTW) is used to adjust for confounding. The primary analysis uses a Cox proportional hazards model, with supplemental analyses using an accelerated failure time model to estimate restricted mean survival time (RMST) at 1 and 2 years. Sensitivity analyses will be conducted to assess the impact of changing the conditions related to non-informative censoring using inverse probability of censoring weights as well as outcome misclassification using probabilistic bias analysis. NO CAL EXTRACCIÓ DE DADES. REUTILITZAREM INSTÀNCIA PRÈVIA DEL CDM DE ConcePTION (no omplim l’apartat de variables de SIDIAP).

Antecedents: La gota afecta un 2,5% de la població de més de 15 anys al nostre entorn (1). La seva incidència està augmentant degut bàsicament a l’envelliment de la població i els canvis en l’estil de vida en tot el món desenvolupat (2). La manifestació clínica més característica és la pruaga, però si no es tracta els episodis d’artritis són poliarticulars i apareixen els tofus i la destrucció articular. A més, avui dia, no tenim dubte que la gota s’associa a un augment de risc cardiovascular, empitjorament de la funció renal i augment de la mortalitat (3,4). Malgrat tenir una rellevància creixent i tenir un tractament conegut i efectiu, és una malaltia infratractada (5,6). Hi ha poques dades epidemiològiques o de característiques clíniques de malalts gotosos en el nostre entorn i a l’atenció primària.
– Objectiu: Avaluar l’ús dels tractaments hipouricemiants en els pacients amb gota a l’atenció primària de Catalunya i descriure les seves característiques clíniques i sociodemogràfiques.
– Metodologia: Estudi observacional longitudinal de cohorts retrospectives de base poblacional.
– Determinacions: Edat, sexe i índex socioeconòmic. Anys d’evolució de la malaltia, nivells d’uricèmia, filtrat glomerular i IMC. Comorbiditats: hipertensió, diabetis mellitus tipus 2, dislipèmia, cardiopatia isquèmica, obesitat, malaltia cerebrovascular, malaltia renal crònica. Consum de tabac i alcohol. Tractament hipouricemiant i amb colquicina: principi actiu i dosi, duració del tractament, període d’exposició, adherència al tractament hipouricemiant. Altres tractaments. Mortalitat.
– Anàlisi estadística: Les característiques de la població es descriuran mitjançant una anàlisi descriptiva. Es calcularà mitja, mediana, valor màxim i mínim i desviació estàndard per a variables contínues i freqüència absoluta i relativa per a variables categòriques. Per a comparar proporcions s’utilitzarà la ?2 i per a mitjanes la prova T de Student. S’estudiarà la prevalença i incidència acumulada del grau de control de la malaltia, mortalitat i tractament reductor de la uricèmia. S’utilitzarà el mètode Kaplan-Meier per a calcular la persistència al tractament hipouricemiant. Tots els resultats seran estratificats per edat, sexe i estatus socioeconòmic.
– Resultats esperats, aplicabilitat i rellevància: S’espera que els pacients amb gota estaran infratractats, amb comorbiditat i mortalitat altes. Aquests resultats ens ajudaran a identificar punts de millora i seran aplicables a l’atenció primària del nostre país. Serà la primera cohort de malalts gotosos de Catalunya.

La insuficiència cardíaca (IC) es classifica habitualment segons la fracció d’ejecció del ventricle esquerre (FEVE), de manera que es diferencien tres fenotips; IC amb FEVE reduïda (IC-FEr), quan és = 40%, IC amb FEVE lleugerament reduïda o intermèdia (IC-FEIr), quan està entre 41-49%, i IC amb FEVE conservada (IC-FEc), si FEVE = 50%. També és habitual utilitzar la classificació funcional de la New York Heart Association (NYHA) per descriure el grau d’IC, basada en la gravetat dels símptomes.
L’objectiu del tractament de la IC és reduir la mortalitat, reduir el risc d’hospitalitzacions per descompensació de la malaltia i millorar la simptomatologia. El tractament farmacològic recomanat segons l’evidència científica varia segons el fenotip d’IC.
L’objectiu d’aquest estudi és classificar els pacients amb diagnòstic d’IC segons la FEVE i descriure les característiques clíniques i sociodemogràfiques d’aquestes persones diagnosticades d’IC i els tractaments farmacològics que s’utilitzen pel maneig de la malaltia.
Es portarà a terme un estudi de cohort amb la base de dades de SIDIAP que inclourà totes les persones amb diagnòstic d’IC a ECAP en el període de 2018 a 2022. Els pacients es classificaran segons la disponibilitat de registre de FEVE i de NYHA a ECAP, i es descriuran les seves característiques sociodemogràfiques i clíniques, a més del tractament farmacològic pel maneig de la IC.
Estem treballant en aquest estudi des de novembre de 2022 i ara sol·licitem les mateixes dades en format OMOP per replicar l’estudi.

Rationale and background: The increasing use of medicines during pregnancy, coupled with a notable lack of safety information for a substantial portion of approved medicines, raises concerns regarding potential teratogenic and neurodevelopmental effects on the fetus. Certain medications with documented long-term teratogenic and neurodevelopmental effects on human fetuses have similarly demonstrated teratogenicity in animal studies. Such correlations emphasize the potential utility of embryo-fetal developmental toxicity (EFDT) studies in identifying medications with lasting effects on children after prenatal exposure. The Dutch National Institute for Public Health and the Environment (RIVM) and the Dutch Medicines Evaluation Board (CBG-MEB) compiled a database comprising rat and rabbit EFDT study outcomes, encompassing 198 European Union (EU) authorized human medicines. This database was used to rank medicines of increased concern, lower concern or minor concern based on malformations and/or embryo-fetal death (MEFL) and exposure safety margins compared to the maximum recommended human dose. In the ConcePTION project, we investigate the long-term effects on offspring after exposure to medications during pregnancy and lactation. Combining data from the animal studies and medication use prevalence data from pregnant women and women of childbearing age could help in prioritizing medicines that pose clinically relevant risk during pregnancy and facilitate the creation of a ranking list for future pharmaco-epidemiological studies.

Research question and objectives: What is the prevalence of prescriptions of medicines known to be associated with developmental toxicity in pregnant women and women of childbearing age?
Primary objectives:
1A. To determine the prevalence of medication use known to be associated with
developmental toxicity in pregnant women, by trimester of pregnancy.
1B. To determine the prevalence of medication use known to be associated with developmental
toxicity in women of childbearing age, by age of the women.
Secondary objective:
2A. To combine medication use prevalence data with pre-clinical data of rat and rabbit teratogens to make a ranking list of medicines known to be associated with developmental toxicity that have a high prevalence of prescription to humans.

Study design: A descriptive retrospective, multi-database cohort study will be conducted.

Population:
The target population will comprise all pregnant women and women of childbearing age registered in the participating data sources between 1 January 2015 – 31 December 2020. The index date for each pregnant women will be the start date of pregnancy. Follow-up continues until end of pregnancy (spontaneous or induced abortion, stillbirth or livebirth). Women of childbearing age will be followed each respective calendar year (2015 till 2020). The follow-up starts at 1 January and ends on 31 December or upon death, migration, becoming pregnant, performing sterilisation, or end of data availability, whichever occurs earliest.

Variables: The ConcePTION algorithm will be used to identify pregnancies. The primary outcome of interest is the prevalence of prescriptions of medicines known to be associated with developmental toxicity. All medicines use refers to prescribed or dispensed medicines as recorded in the participating data sources. All medicines will be identified by Anatomical Therapeutic Chemical (ATC) code. Pregnant women will be considered exposed to the medicines if they received at least one prescription during pregnancy. Women of childbearing age will be considered exposed to the medicines if they had received at least one prescription during follow-up.

Data sources: This study will include data from 4 national healthcare databases in 3 European countries (Italy, Spain, UK), pending feasibility and confirmation.
Study size: The study will include all pregnant women and women of childbearing age identified in the participating data source over a 5 years’ time span.

Data analysis: For objective 1, the prevalence of the medicines of interest will be computed for each data source stratified by trimester of pregnancy. Prevalence will be calculated per 1000 pregnancies with 95% confidence interval. To calculate the prevalence, the numerator will be the number of women having one or more prescription of the specific medicine within a given trimester. The denominator will be the number of women contributing to that trimester. For objective 2, the prevalence of the medicines of interest will be computed for each data source stratified by age. To calculate the prevalence, the numerator will be the number of women having one or more prescription of the specific individual medicines within the given study-period. The denominator will be the total number of women contributing at least one day of person-time to that study period. A sensitivity analysis with >1 prescription will be conducted in both cohorts.

We will use a previous data instance of the ConcePTION CDM, so no new data extraction is needed.

RATIONALE AND BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Abrocitinib received marketing authorization for the European Union (EU) on 09 December 2021 and is indicated for the treatment of moderate to severe AD in adults who are candidates for systemic therapy. To mitigate the risks associated with abrocitinib, required routine RMMs including the SmPC and package leaflet are being employed. In addition to the routine RMMs, additional RMMs (aRMMs) inclulding prescriber’s brochure and patient card, are being implemented in the EU.
RESEARCH QUESTION AND OBJECTIVES: The study objectives are to evaluate, to the extent measurable in the available routinely collected data, indicators of HCPs’ adherence to the RMMs in accordance with the abrocitinib SmPC and prescriber’s brochure, assessed by:
– indicators of adherence to performing laboratory tests of CBC, lipid panel, hepatitis B/C, and TB screening prior to initiation of abrocitinib treatment,
– indicators of adherence to performing laboratory tests of CBC and lipid panel at week 4 (±2 weeks) after initiation of abrocitinib treatment,
– indicators of adherence to consideration of risk factors for VTE, MACE, malignancy and serious infection prior to treatment with abrocitinib,
– indicators of adherence to avoid live attenuated vaccines immediately prior to and during treatment with abrocitinib,
– indicators of adherence to contrainidcations for use during pregnancy,
– indicators of adherence to contraindications for use amog patients with severe hepatic impairment,
– indicators of adherence to no use in patients aged < 18 years, and - indicators of adherence to recommended posology (estimated average daily dose). STUDY DESIGN: This will be a descriptive drug utilization study using secondary data from healthcare databases in Denmark, France, Sweden, Spain and Hungary. POPULATION: The study population will include patients with a dispensing of abrocitinib as recorded in routinely collected electronic healthcare data in Denmark, France, Sweden, Spain and Hungary during the study period (study start: country-specific aRMM distribution [01 March 2022, Sweden; 09 March 2022, Denmark; 31 July 2022, France; 30 Jan 2023, Spain; September 2023 (estimated), Hungary]; study end: December 2026). These countries have universal healthcare. VARIABLES: The study will collect all relevant data including patient demographics, comorbidities, prescription medications, vaccine administration, and laboratory testing prior to the initiation of abrocitinib and during treatment with abrocitinib to address the study objectives. DATA SOURCES: This study will utilize routinely collected electronic healthcare data from national or regional population-based electronic healthcare registers in Denmark, Sweden and Spain and an administrative healthcare databases in France and Hungary. STUDY SIZE: All patients initiating abrocitinib during the study period will be included. DATA ANALYSIS: Data will be analysed in each country separately using a common protocol, database-specific definitions of the study variable, and common analysis strategy. The main indicators will be proportions of abrocitinib users with a given indicator of aRMM adherence.

This tender is composed of two objectives:
1. Objective 1: To describe utilisation of antiepileptics in individuals of childbearing age, pregnant, and male individuals. This objective will be described in WorkPackage (WP) 1. There is a specific protocol for WP1. The development of WP1 protocol is one of the deliverables of the project.
2. Objective 2: To assess the feasibility of estimating the risk of adverse pregnancy, neonatal and child outcomes following in utero and paternal exposures to antiepileptic drugs. This objective will be assessed in WP2. Initially, only databases with developed father-child linkage developed were expected to participate. In the end, EMA required all databases involved in WP1 to participate also in WP2. WP2 does not require a data extraction, as it will answer the question whether data sources are fit for purpose for studies assessing adverse pregnancy, neonatal and child outcomes following either ASM exposure through the mother, or periconceptional ASM exposure through the father. There is a specific protocol for WP2. The development of WP2 protocol is one of the deliverables of the project.
Prototol 1 – WP1: THE UTILISATION OF ANTISEIZURE MEDICATIONS IN MEN, WOMEN OF CHILDBEARING AGE, AND PREGNANT WOMEN: A MULTI-DATABASE STUDY FROM 7 EUROPEAN COUNTRIES.
Background: Currently there is substantial evidence on teratogenicity of several antiseizure medications (ASMs) and a potential increased risk of neurodevelopmental disorders in young children exposed in utero to ASMs. Recently, few evidence has emerged expanding this risk also when there was a paternal exposure before conception. On that line, EMA asked for an updated evaluation on trends in use of various ASMs and related drugs in pregnant women, in other women of childbearing potential, and in men.
Objectives: The main objective of this study is to describe the utilisation of ASMs and related drugs (i.e., antiepileptics (ATC codes N03A), gabapentinoids (N02BF), and all benzodiazepines with antiepileptic properties) in pregnant women, other women of childbearing potential (12-55 years of age), and men (12 years and older). It has the following sub-objectives: 1.1) To estimate the annual incidence and prevalence rate of ASM use in women of childbearing potential and in men; 1.2) To describe treatment duration, discontinuation, and treatment switches to other ASMs or alternative medications and polytherapy in women of childbearing potential and men; 1.3) To estimate incidence and prevalence of specific ASM use in up to one year prior to and during the pregnancy period in all pregnant women; 1.4) To estimate and compare discontinuation, treatment switches to other ASMs or alternative medications and polytherapy among pregnant women in the 12-10, 9-7, 6-4, and 3 months prior to pregnancy or during first, second and third pregnancy trimesters; 1.5) To estimate dose changes of ASMs in women prior to and during pregnancy.
Study Design: Retrospective population-based cohort study.
Exposure and outcomes: The main exposures of interest are ASMs (N03A), including gabapentinoids (N02BF) and benzodiazepines with antiepileptic properties. The drug utilisation outcome measures will be the incidence and prevalence of ASM use among pregnant women, other women of childbearing potential, and men, treatment duration of ASM, discontinuation of ASMs, initiation of ASM use during pregnancy, switching to another ASM or an alternative medication, dose changes of ASMs before and during pregnancy, and polytherapy of ASMs.
Data Analysis: According to sub-objectives stated above, statistical estimates will be produced, such as descriptives (counts, percentages), distributions (mean, percentiles), rates (incidence, prevalence), or other relevant estimates. Various visualisations (e.g., flow diagrams, line and bar charts, and Sankey diagrams) will be used to depict the findings. This will be conducted using a common R script.
Limitations: Our operational definitions of treatment episodes with a grace period of 30 days, temporary break (between 30-120 days of no new prescription/dispensing), ASM discontinuation (no new record after 90 days), and switching from an ASM to another ASM or an alternative medicine might not reflect the exact clinical scenarios in case of all ASMs, especially when using data from diverse EHDs. One especial case would be misclassification of prevalent users as incident users due to considering not long enough look-back periods. Due to this, we will not estimate incident use of ASMs among women and men of childbearing potential and initiation of ASM during pregnancy in data sources EFEMERIS and THL that we only have 2.5 or 3-months look-back data for medications. But the overall approach is based on prior drug utilisation studies on the same topic,8,28 and same definitions for all ASMs across all centres, which considering the limitations and data quality will assist in comparability of findings. Another limitation could be operational definitions for high, medium, and low daily doses of ASMs based on DDD data, which might not always reflect the actual clinical situation. But considering the diversity of data sources and healthcare systems involved, this seems the only feasible option in such a multi-database study. Also, capturing the right doses would be difficult when prescriptions are not renewed but patients were using the old prescription with new instructions from clinician, which is not visible in all our included data sources. This will be taken into account when interpreting findings from the dose analyses.
Protocol 2 – WP2: FEASIBILITY OF ESTIMATING THE RISK OF ADVERSE PREGNANCY, NEONATAL AND CHILD OUTCOMES FOLLOWING EITHER IN UTERO ASM EXPOSURE THROUGH THE MOTHER, OR PERI-CONCEPTIONAL ASM EXPOSURE THROUGH THE FATHER
Rationale and background: Evidence shows that certain ASMs such as valproate, pose teratogenic and neurodevelopmental risks during pregnancy. Conflicting findings also suggest potential neurodevelopmental impacts from paternal ASM exposure pre-conception. Thus, it is critical to assess the feasibility of causal studies on ASM exposure, especially given the complexity of father-child data linkage.
Research question and objectives: This study aims to understand whether data sources can be used to study the effects of maternal and paternal exposure to ASM, on pregnancy, neonatal and child outcomes. For this main objective, the following sub-objectives will be addressed:
a. To estimate the availability of relevant information/characteristics for pregnant women, using 15 different parameters that will inform the assessment of fitness for purpose.
b. To estimate availability of relevant information/characteristics for men and linkage with pregnancies, using 9 different parameters that will inform the assessment of fitness for purpose.
c. To estimate availability of relevant information/characteristics for neonates/children, using 17 parameters and comparing them between those that can and cannot be linked to mother and/or father where possible.
d. To assess fitness for purpose to different types of studies of pre-conceptional/prenatal exposure to antiepileptics and the development of adverse pregnancy and child outcomes.
Study design: This is a retrospective cohort study to assess the suitability of the available databases for ASM exposure studies, aligning with the study’s fit for purpose evaluation.
Population: The source population comprises all persons of childbearing age who are registered with the data sources that participate in this study. From the source population, we will select study cohorts for each of the different sub-objectives.
Variables: The main exposures of interest are ASMs (N03A) and gabapentinoids (with ATC code N02BF) and all benzodiazepines with antiepileptic properties. Outcome parameters will be considered per subobjective. Clinical outcomes of interest will include pregnancy outcomes (i.e., spontaneous pregnancy loss, stillbirth, preterm birth) neonatal/child outcomes (e.g., small gestational age, congenital anomalies, adverse neurodevelopment).
WP2 does not require a data extraction, as it is a study to assess the fit for purpose of the databases for assessing adverse pregnancy, neonatal and child outcomes following either ASM exposure through the mother or periconceptional ASM exposure through the father.
Data analysis: For objective a-c we will estimate the 41 feasibility parameters using descriptive analyses and visualizations. For objective d, we will use the parameters from objectives a-c plus metadata on the data sources and assess the fitness-for-purpose of the data instance by using, implementing, and adapting the framework from Gatto and colleagues.
Limitations: Methods for descriptive analysis have been employed in previous studies undertaken across the ConcePTION project, EU PE&PV and VAC4EU networks (Durán et al., 2023a; Hurley et al., 2023; Abtahi et al., 2023; Durán et al., 2023b). This protocol aims to leverage existing tools available tools and algorithms, developed by the aforementioned enterprises, including the ConcePTION CDM, the pregnancy algorithm, the INSIGHT quality checks, code lists and algorithms, as well as component analyses and the analytical pipeline and functions. Differences between data sources will be described transparently. The aim is to describe and appraise mother-child and father-child linkage, both deterministic and probabilistic, that has been established thus far across each data source. We also aim to investigate novel improvement in linkage using additional parameters available in EHR data. It is possible that improvements in probabilistic linkage will not be possible due to characteristics of available data fields, or because linkage will not improve materially with inclusion of these additional data fields. Exploration of parental linkage will be described transparently, regardless of whether improvement in linkage is possible. Due to limited budget and the scope of work, we will not be able to validate any of the linkages nor outcomes.

Rationale and background: Paxlovid consists of nirmatrelvir (formerly PF-07321332), a potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, co-administered with a low dose of ritonavir, which acts as a pharmacokinetic enhancer, orally twice a day for 5 days. Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
The safety of Paxlovid in pregnant women is not known. The post-authorisation safety study (PASS) of Paxlovid in pregnant women is a regulatory commitment to the European Medicines Agency (EMA) and the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA).
Research question and objectives: The primary study objective is to estimate the birth prevalence, prevalence ratio, and prevalence difference of the following adverse pregnancy, offspring, and maternal outcomes in women with COVID-19 who are exposed to Paxlovid during pregnancy compared with those in women with COVID-19 who are exposed to molnupiravir (or other comparable medications for COVID-19), where available, during pregnancy or to women with COVID-19 unexposed to any study medications during pregnancy:
Pregnancy outcomes
• Spontaneous abortion
• Elective termination
• Stillbirth
• Preterm delivery
Offspring outcomes
• Major congenital malformations
• Intrauterine growth retardation/small for gestational age
Maternal outcomes
• Gestational diabetes
• Gestational hypertension
• Postpartum haemorrhage
• Maternal death
The secondary study objective is to assess maternal exploratory outcomes in outpatient and inpatient settings as available that will be identified based on conditions appearing in the study population after exposure to Paxlovid.
Study design: The study will focus on pregnant women. Within this population, there will be a descriptive analysis and comparative analyses. Molnupiravir, an antiviral with a similar recommended usage, will be used as an active comparator in the data sources in which it is available; other drugs may be incorporated as active comparators as more information becomes available. At the time of preparing this protocol, molnupiravir was not utilised or its use was not captured by some of the data sources (eg, France and Information System for Research in Primary Care [SIDIAP] in Catalonia, Spain). Therefore, a second comparator group is included in the study: individuals with COVID-19 unexposed to any study medication. Other medications to treat COVID-19 will be considered as active comparators in the future.
The study period will start on 01 January 2022 (in alignment with regulatory authorisation and launch in Europe) and end as late as possible.
Population: The target study population will be individuals with COVID-19 exposed to Paxlovid or comparator drug molnupiravir or other comparable medications and individuals unexposed to Paxlovid, molnupiravir, or other comparable medications (the unexposed comparison group), while they are pregnant.
Data sources: As of 20 September 2022, the MAH has confirmed that Paxlovid has been supplied to France, Germany, Italy, Spain, Slovenia, Sweden, and the UK, initially or continuing under special government contracts, resulting in different distribution and reimbursement channels being used and subsequent challenges capturing its prescription and distribution. Current information is that prescribed/dispensed Paxlovid should be captured in existing electronic population data sources in France, Spain, and the UK. The Italian Medicines Agency (AIFA) established a national registry for Paxlovid and other antivirals to treat COVID-19. At the time of this writing, capture of Paxlovid dispensing/prescriptions in the existing electronic data sources commonly used for pharmacoepidemiological research in Italy at this moment is expected to be minimal. As long as the German government continues to cover payments for Paxlovid, it is expected that Paxlovid prescriptions will not be captured in the German Statutory Health Insurance data sources.
The proposed data sources are the French Administrative Healthcare Database (SNDS), SIDIAP (Catalonia, Spain), and Clinical Practice Research Datalink–Aurum (CPRD Aurum) (UK). The UK OpenSAFELY data source and the AIFA patient registry will continue to be explored as potential supplementary data sources for this study.
Study size: All individuals meeting eligibility criteria during the study observation period will be included. As the summaries of product characteristics (SmPCs) recommend against use in pregnancy, Paxlovid exposure in this population is anticipated to be small.
Data analysis: Study data will be analysed as a cohort. Descriptive baseline characteristics will include tabulations of age, sex, comorbidities, selected concurrent medications, COVID-19 vaccination status, history of COVID-19, current COVID-19 status and setting of Paxlovid use (among Paxlovid users). Comparative analyses will be based on the estimation of risk/prevalence, risk/prevalence ratios, and risk/prevalence differences. Comparative analyses will control for measured confounding within each data source. Aggregated results from each data source will be combined using meta-analytic techniques as numbers allow. If a study population is too small, analyses will be only descriptive; pooling of results from various data sources will be undertaken only if at least 3 independent data points are available.

Study to be conducted with the ConcePTION common data model. We plan to extract the data for both Paxlovid protocols (pregnancy & liver_renal populations) in a unique extraction (one in 2024 for interim report 1, another in 2025-26 for interim 2 and final report), but we present two different application forms for each protocol endorsed by PRAC (EMA).
Paxlovid is dispensed in a specific circuit in Spain, not in the usual electronic prescription.

Rationale and background: Paxlovid consists of nirmatrelvir (formerly PF-07321332), a potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, co-administered with a low dose of ritonavir, which acts as a pharmacokinetic enhancer, orally twice a day for 5 days. Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
The safety of Paxlovid in individuals with hepatic or renal impairment is not known. Assessing the safety of Paxlovid among individuals with moderate or severe hepatic or renal impairment is a regulatory commitment to the EMA.
Research question and objectives:
• What is the safety profile of Paxlovid in patients with COVID-19 and moderate or severe hepatic impairment?
• What is the safety profile of Paxlovid in patients with COVID-19 and moderate or severe renal impairment?
For the population of individuals with moderate or severe hepatic impairment, the objectives are:
Primary objectives
• To assess the safety of Paxlovid relative to the comparator populations prescribed molnupiravir (or other comparable medications for COVID-19), where available, and to unexposed patients with COVID-19.
• To assess side effects resulting from drug overexposure due to impaired liver function and with regard to severity and frequency compared with comparator groups. Safety outcomes for primary objectives are all safety events in outpatient and inpatient settings, as available, including the following safety outcomes of special interest:
• Hepatic transaminase elevations, clinical hepatitis, or jaundice
• Severe vomiting, nausea, diarrhoea, or abdominal pain
• Dysgeusia, headache, or hypertension
• Anaphylactic reactions
Secondary objective
• To assess all safety events included in the primary objective that require hospitalisation or emergency department visits
For the population of individuals with moderate or severe renal impairment, the objectives are:
Primary objectives
• To assess the safety of Paxlovid relative to the comparator population prescribed molnupiravir (or other comparable medications for COVID-19), where available, and to unexposed patients with COVID-19.
• To assess side effects resulting from drug overexposure due to impaired renal function and with regard to severity and frequency compared with comparator groups.
Safety outcomes for primary objectives are all safety events in outpatient and inpatient settings, as available, including the following safety outcomes of special interest:
• Severe vomiting, nausea, diarrhoea, or abdominal pain
• Dysgeusia, headache, or hypertension
• Anaphylactic reactions
Secondary objective
• To assess all safety events included in the primary objective that require hospitalisation or emergency department visits
Study design: The study will employ a cohort design and will make secondary use of multiple sources of data from electronic health records and/or claims data in European countries. Data sources currently selected have the ability to capture Paxlovid exposure where the target populations, study outcomes, and key covariates can be ascertained. The feasibility component of this research programme will provide counts of the target population, separately for Paxlovid users, users of molnupiravir, users of other comparable medications (Section 9.1.2, Table 2), and the unexposed comparator group. Relevant patient characteristics will be presented for each exposure group in the target population to allow an assessment of the feasibility of comparative analyses. Molnupiravir, an antiviral with a similar recommended usage, will be used as an active comparator in the data sources for which it is available; other drugs may be incorporated as active comparators as more information becomes available. At the time of preparing this protocol, molnupiravir was not utilised, or its use was not captured by some of the data sources (eg, France and Information System for Research in Primary Care [SIDIAP] in Catalonia, Spain). Therefore, a second comparator group is included in the study: individuals in the target populations with COVID-19 who had not received Paxlovid, molnupiravir or other comparable medications, referred to as “unexposed patients”. The study period will start on 01 January 2022 (in alignment with regulatory authorisation and launch in Europe) and end based on the calendar period coverage at the time of the last data extraction.
Population: The target study populations are individuals with moderate or severe hepatic or renal impairment with COVID-19 exposed to Paxlovid or comparator drug molnupiravir or other comparable medications, and individuals unexposed to Paxlovid, molnupiravir, or other comparable medications (the unexposed comparison group).
Data sources: As of 30 September 2022, the MAH has confirmed that Paxlovid has been supplied to France, Germany, Italy, Spain, Slovenia, Sweden, and the United Kingdom (UK), initially or continuing under special government contracts, resulting in different distribution and reimbursement channels being used and subsequent challenges capturing its prescription and distribution. Current information is that prescribed/dispensed Paxlovid should be captured in existing electronic population data sources in France, Spain, and the UK. The Italian Medicines Agency (AIFA) established a national registry for Paxlovid and other antivirals to treat COVID-19. At the time of this writing, capture of Paxlovid dispensing/prescriptions in the existing electronic data sources commonly used for pharmacoepidemiological research in Italy is expected to be minimal. As long as the German government continues to cover payments for Paxlovid, it is also expected that Paxlovid prescriptions will not be captured in the German Statutory Health Insurance data sources.
The proposed data sources for this study are the French Administrative Healthcare Database (SNDS), SIDIAP (Catalonia, Spain), and Clinical Practice Research Datalink Aurum (CPRD Aurum) (UK). The UK OpenSAFELY data source and the AIFA patient registry will continue to be explored as potential supplementary data sources for this study.
Study size: All individuals meeting eligibility criteria during the study observation period will be included. As the summaries of product characteristics (SmPCs) caution (EU) or contraindicate (UK) use in severe hepatic or renal impairment, Paxlovid exposure in these populations is anticipated to be small.
Data analysis: Study data will be analysed as a cohort. Descriptive baseline characteristics will include tabulations of age, sex, comorbidities, selected concurrent medications, COVID-19 vaccination status, history of COVID-19, current COVID-19 status and setting of Paxlovid use (among Paxlovid users). Comparative analyses will be based on the estimation of risk ratios and risk differences. Comparative analyses will control for measured confounding within each data source. Aggregated results from each data source will be combined using meta-analytic techniques as numbers allow. If a study population is too small, analyses will be only descriptive; pooling of results from various data sources will be undertaken only if at least 3 independent data points are available.

Study to be conducted with the ConcePTION common data model. We plan to extract the data for both Paxlovid protocols (pregnancy & liver_renal populations) in a unique extraction (one in 2024 for interim report 1, another in 2025-26 for interim 2 and final report), but we present two different application forms for each protocol endorsed by PRAC (EMA).
Paxlovid is dispensed in a specific circuit in Spain, not in the usual electronic prescription.

Antecedents: Des de la comercialització dels inicialment anomenats com a nous anticoagulants orals i actualment coneguts com anticoagulants orals directes (ACOD), ha disminuït l’ús dels fàrmacs antagonistes de la vitamina K (AVK) acenocumarol i warfarina.
La seva fàcil posologia i els aparents millors resultats en seguretat han fet dels ACOD una alternativa realment interessant per a pacients amb necessitats d’un tractament anticoagulant, p.ex pacients amb una fibril·lació auricular no valvular (FANV). Els ACOD no estan exempts de risc d’hemorràgia, però també han aparegut altres problemes de seguretat envers el potencial d’interacció amb altres medicacions freqüentment prescrites a pacients anticoagulats. Tant des de la perspectiva farmacocinètica com des de la farmacodinàmica els ACOD poden interaccionar amb altres medicacions disminuint la seva efectivitat (risc trombòtic) o incrementant el risc d’hemorràgia.
Hipòtesis: Les interaccions farmacològiques amb els ACOD resulten en un augment del risc d’efectes adversos, tant del risc d’hemorràgia com del risc d’esdeveniments trombòtics per una disminució de la seva efectivitat.
Objectius: Quantificar el risc de les interaccions farmacològiques (farmacocinètiques o farmacodinàmiques) més rellevants dels ACOD actualment comercialitzats a Catalunya i la seva repercussió clínica en forma d’esdeveniments hemorràgics o trombòtics durant 2014-2021.
Metodologia: Estudi observacional analític amb disseny autocontrolat. Formaran part de la cohort aquells individus que presentin un diagnòstic de FANV amb almenys 3 mesos d’exposició a un ACOD (dabigatran, rivaroxaban, apixaban, edoxaban). Els individus que entrin a la cohort s’analitzaran en base a la resta de medicacions que consumeixen amb especial èmfasi en fàrmacs que poden alterar el metabolisme dels ACOD a través del citocrom P-450 (ritonavir, rifampicina i dexametasona entre altres) o que per les seves característiques farmacodinàmiques puguin augmentar el risc d’hemorràgia (AINEs, ISRS, corticoides o antiagregants entre altres grups) o disminuir-lo (inhibidors de la bomba de protons). S’analitzarà el risc d’esdeveniments hemorràgics o trombòtics que impliquin l’ingrés a un centre hospitalari amb una alta d’hemorràgia rellevant, hemorràgia gastrointestinal, hemorràgia intracranial, ictus o embòlia sistèmica.
Dades: dades de prescripció, dispensació i facturació farmacèutica d’ACOD i els grups d’interès per la seva capacitat d’interacció (Sistema Integrat de Recepta Electrònica o SIRE i el Registre de Pacients i Tractaments o RPT que conté la Facturació de Medicaments Hospitalaris de Dispensació Ambulatoria o MHDA) amb data i posologia. Dades del CMBD-HA.

Tots els nous hipoglucemiants no insulínics (HNI) han demostrat eficàcia en la reducció de l’HbA1c (major o menor efecte glucèmic segons el grup farmacològic) i han demostrat no associar-se a pitjors resultats de morbimortalitat CV en els estudis de seguretat CV requerits per les agències reguladores. Tot i que alguns d’aquests estudis amb ISGLT2 i ARGLP1 suggereixen que aquests fàrmacs podrien tenir beneficis en morbimortalitat CV, fins ara no està clarament establert quin és l’impacte clínic real que tenen en el tractament de la DM2 en la pràctica clínica del nostre entorn. No hi ha estudis poblacionals en el nostre entorn que hagin analitzat l’associació entre la introducció dels nous grups d’ISGLT2 i ARGLP1 i els esdeveniments clínics.
Objectiu general: estudiar l’associació entre l’evolució de la utilització dels diferents hipoglucemiants i l’evolució dels resultats en salut en la població de pacients amb DM2 de Catalunya en el període 2015-2020.
Es tracta d’un estudi observacional de disseny ecològic. A més, es durà a terme una anàlisis descriptiva dels resultats en salut en els diferents anys segons el tipus de tractament hipoglucemiant. Totes les dades provenen de fonts secundàries: fitxer de prestacions farmacèutiques del CatSalut, SIDIAP, CMBDs, RCA.
Els objectius a analitzar amb dades de SIDIAP són:
– Descriure l’evolució en el percentatge de pacients controlats (HbA1c < 7%) i de les HbA1c mitjanes en el període 2015-2020 en la població de pacients amb DM2 (amb tractament o sense) i en la població de pacients amb DM2 tractats amb hipoglucemiants. - Descriure l'evolució en el percentatge de pacients controlats (HbA1c < 7%) i de les HbA1c mitjanes en el període 2015-2020 en la població de pacients amb DM2 tractats amb hipoglucemiants en funció del tipus de tractament: HNI en monoteràpia, combinacions d'HNI, insulina en monoteràpia i combinacions d'HNI amb insulina. - Descriure l'evolució en el percentatge de pacients amb obesitat (índex de massa corporal [IMC] ? 30 Kg/m2) i de les mitjanes d'IMC en el període 2015-2020 en la població de pacients amb DM2 (amb tractament o sense) i en la població de pacients amb DM2 tractats amb hipoglucemiants. Paraules clau: diabetis mellitus tipus 2, hipoglucemiants no insulínics, evolució, mortalitat, esdeveniments cardiovasculars, HbA1c.

Rationale and background: The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), has led to a global pandemic. AZD1222 is a vaccine developed to prevent COVID-19. Now known as COVID-19 Vaccine AstraZeneca, the vaccine has received emergency use authorisation in the United Kingdom (UK) and conditional approval by the European Commission. Several important potential risks have been identified based on the experience of other non-COVID-19 vaccines. The clinical development programme also had limited enrolment of certain patient populations, including pregnant or breastfeeding women, individuals who are immunocompromised, frail persons with comorbidities, those with autoimmune or inflammatory disorders, and use with other vaccines such as an influenza vaccine.
Research question and objectives: What are the incidence rates (IRs) of safety events of interest (based on adverse events of special interest [AESIs]) among individuals vaccinated with AZD1222 and in individuals who have not received any vaccination for COVID-19, overall and in subpopulations of interest, within selected European data sources? How do the IRs compare with one another? What are the baseline characteristics of individuals who received at least one dose of AZD1222? How many of them received a second dose of a COVID-19 vaccine, which vaccine did they receive, and when did they receive it?
Study design: A multi-country, retrospective cohort design will be used to estimate the incidence of AESIs after receiving AZD1222 and will compare this incidence with that occurring in an unvaccinated comparator group. Where appropriate, the study will also use a self-controlled risk interval (SCRI) design. The study period will start on 04 January 2021, when the vaccine was first used in the UK, and will end approximately 24 months after it is introduced in the last country among participating data sources.
Population: The source population will comprise all individuals registered in each of the health care data sources. An exposed cohort will be identified based on first vaccination with AZD1222 (index date). A concurrent comparator population will be identified among subjects who have not received any vaccination for COVID-19 matched on the vaccinee’s index date, age, and gender.
Variables: Receipt of AZD1222, other SARS-CoV-2 vaccines, and dates of vaccination will be obtained from all possible sources that capture COVID-19 vaccination, such as pharmacy dispensing records, general practice records, and immunisation registers. Safety outcomes include safety concerns and other AESIs. These outcomes will be identified using algorithms based on codes for diagnoses, procedures, and treatments in electronic data, and they will be defined uniformly across the data sources to the fullest extent possible. Operational case definitions from the ACCESS (vACcine Covid-19 monitoring readinESS) project will be implemented for the AESIs for which they have been developed.

Desarrollo de algoritmos parobabilísticos para estimación de tratamientos combinados en registros electrónicos de salud.

El algoritmo usa datos de fármacos, prescripciones principalmente, y nos permitirá detectar de forma automática cuando se observan tratamientos combinados, su duración, posibles cambios y discontinuaciones.

Para poder publicar el método, se ha diseñado un ensayo de validación que requiere de datos reales, en este caso los datos de la extracción de SIDIAP del proyecto titulado ‘Características sociodemográficas, clínicas y farmacológicas asociadas con el pronostico en pacientes con infección por SARS-CoV-2 (4R20/029, SIDIAP 396)’

La incontinència urinària (IU) és la pèrdua involuntària d’orina i pot ser d’esforç (IUE), d’urgència (IUU) o mixta (IUM). Aquest estudi té com a objectius:
– Descriure la població que inicia tractament amb antiespasmòdics urinaris (anticolinèrgics urinaris o mirabegró): característiques sociodemogràfiques, comorbiditats, comedicacions, diferències per sexe i edat.
– Descriure l’ús d’absorbents d’orina per al tractament de la IU: número de pacients que utilitzen bolquers i reben tractament farmacològic simultàniament.
– Descriure principi actiu, dosi i durada dels tractaments farmacològics de la IU.
– Analitzar canvis de tractament i combinacions de principis actius.
– Estimar l’adherència al tractament farmacològic.
– Estimar la càrrega anticolinèrgica en aquells pacients tractats amb fàrmacs antimuscarínics i mirabegró.
La població d’estudi estarà formada per aquells pacients amb una nova prescripció de fàrmacs antiespasmòdics urinaris durant el període 2015-2017 i amb seguiment fins a 31/12/2018.

RATIONALE AND BACKGROUND
Irritable bowel syndrome (IBS) is a chronic, relapsing gastrointestinal condition characterised by abdominal pain, bloating, and changes in bowel habits. Prevalence estimations vary with the diagnostic criteria used, and in the United Kingdom (UK) were estimated between 9.5% and 22%. IBS can be classified according to Rome III criteria on the basis of the stool?s characteristics: IBS predominantly with diarrhoea (IBS-D); IBS predominantly with constipation (IBS-C); and IBS with mixed bowel habits (IBS-M). Approximately one-third of IBS patients have each type of the disease.
The commercialisation of linaclotide (Constella®), a guanylate cyclase-C receptor agonist with visceral analgesic and secretory activities, was approved as the first medicine authorised for the symptomatic treatment of moderate-to-severe IBS-C in adults in the European Union (EU).
Therefore, this study is planned to assess the safety of linaclotide in terms of the risk of severe complications of diarrhoea (SCD) during treatment and other risk factors among patients with IBS-C in Spain.
RESEARCH QUESTION AND OBJECTIVES
This study will occur over two phases. In Phase I, we will validate an algorithm for identifying SCD. In Phase II, we will use either a cohort design (Phase IIa) or a case-control design (Phase IIb) depending on the results the validation study to investigate whether use of linaclotide is associated with an increased risk of SCD.
The specific objectives of the study are:
Phase I: Validation Study
– Estimate the incidence of diarrhoea and identify patients experiencing severe complications of diarrhoea (SCD) among patients with IBS-C
– Validate a proposed diagnostic algorithm for SCD among patients with IBS-C
Phase IIa: Cohort Study
If a PPV>95% is achieved in the validation study, then we will use a cohort design to:
– Estimate the incidence of SCD among IBS-C patients prescribed linaclotide overall and stratified by groups of interest (i.e. patients ?65 years, patients with hypertension, diabetes, or cardiovascular disease diagnostic codes)
– Identify risk factors for SCD, with linaclotide and laxative use being the key exposures of interest
Phase IIb: Case-control Study
If a PPV<95% is achieved in the validation study, then Phase IIb will be executed, in which a matched case-control design will be used to: - Identify risk factors for SCD, with linaclotide and laxative use being the key exposures of interest The rationale for this study design is that if the results from the validation study show that the SCD algorithm has a good performance, we can implement this algorithm to identify our outcome of interest within the entire study population and conduct a classic cohort analysis. However, if the algorithm has poor performance, then we will only be able to utilise confidently the data within the validation sample for the implementation of a matched case-control study. STUDY DESIGN The final decision on study design will be made following the validation stage. If the PPV is >95% then a cohort study design will be used, otherwise a matched case-control study will be used.
POPULATION
This study will use observational data from and Spain. The study population will be a cohort of IBS-C patients. Patients with less than 12 months of computerised records prior to IBS-C cohort entry date or no follow-up time will not be included.
VARIABLES
Users will be classified as current, never and past users. For Phase IIa (cohort study), these exposures will be defined based on drug prescriptions in a time-updated manner The outcomes of interest are severe complications of diarrhoea including dehydration that requires intravenous rehydration, dehydration that requires oral rehydration with solutions of electrolytes, electrolyte imbalance (potassium and sodium), oliguria, anuria, new onset-thromboembolism, new-onset orthostatic hypotension, new-onset syncope, new-onset dizziness, new-onset vertigo, acute renal failure, hypovolemic shock, hospitalisation due to diarrhoea, stupor, coma, or death.
All variables will be identified using diagnostic and procedure codes from general practitioner (GP) electronic medical records. IBS type and safety outcomes will be validated through a questionnaire to physicians treating the cases and controls included in the study.
DATA SOURCES
This part of the study will utilise data from the Information System for the Development of Research in Primary Care (SIDIAP). SIDIAP is a primary care database that collects longitudinal data from electronic medical records (EMRs) from 274 primary care centres in Catalonia since 2006, representing approximately 12% of the Spanish population. Data from primary care, specialised care, hospitals, and pharmacies are available, as well as patient characteristics like gender and date of birth, GP-diagnosed conditions, GP prescriptions, prescription dosing and size, date of prescription and dispensation, laboratory test results, other procedures, specialist referrals and diagnosis, hospital referrals, hospital procedures and discharge diagnosis, death date, and pregnancy information. GP diagnoses are coded following the ICD-10 codes, and hospital admissions are classified following the International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9). Since 2018, SIDIAP no longer allows the possibility to contact physicians for extracting extended additional information on the patient through long questionnaires. However, there is the possibility of a text review of the primary care records. This text review can be used to validate cases of interest and it would be conducted by IDIAP?s clinical researchers. For this study, it is recommended by the data custodians that a review of free-text in the patient?s medical records is conducted to improve the validity of the actual study, in place of the previously planned validation strategy using questionnaires to GPs. This free-text review will be made after an anonymisation process of the clinical records and a natural language processing of the text.
STUDY SIZE
From the linaclotide drug utilisation study we know that the total number of linaclotide users in SIDIAP between 2014 and 2017 was 1,854 patients.
Within the IBS-C cohort, we expect to accrue a non-trivial number of cases (e.g., 94 cases of SCD with an incidence of 0.05% among IBS-C patients) and the same number (or larger) of controls (e.g., that would provide 80% power [or greater] to detect an OR=4 [or larger] associating SCD with a risk factor present in 5% of controls [notice that we expect exposure to linaclotide in approximately 5% of the cohort]).
DATA ANALYSES
Patient characteristics at cohort entry date will be described for the full cohort of patients with IBS-C, as well as incidence rate of diarrhoea.
If the results of the validation of cases and controls are satisfactory (positive predictive value of EMRs in Spain ? 95% and negative predictive value ? 99%), then information from the whole cohort will be used to estimate incidence rates for those groups of patients with IBS-C prescribed linaclotide and those who are potentially at increased risk of SCD and prescribed linaclotide. The crude incidence of diarrhoea and of severe complications of diarrhoea will be described by calculating the proportion of patients with IBS-C experiencing diarrhoea and SCD, respectively, and their associated 95% confidence intervals (CIs). Crude incidence rates of SCD will be also calculated.
Additionally, the hazard ratios of SCD and the exposures of interest (mainly prescription of linaclotide) will be estimated using Cox proportional hazard models.
If the results of the validation of cases and controls in Spain are not satisfactory (positive predictive value of our outcome algorithm in Spain < 95% or negative predictive value < 99%), only the nested case-control study will be performed and ORs of SCD and the same exposures of interest will be estimated using data from cases and matched controls by applying conditional logistic regression analysis. The goal is to assess SCD among patients who were treated with linaclotide, were ?65 years old, and had history of hypertension, diabetes or cardiovascular disease diagnostic codes (i.e., SCD occurrence is the outcome variable [yes/no] and the independent variables of main interest are whether the patient has a prescription for linaclotide, a prescription for laxatives, the patient is ?65 years old, and the patient has hypertension, diabetes, or cardiovascular disease diagnostic codes, all of them at index date, or not, controlling for potential confounders). Statistical analyses will be conducted using R statistical software.

Justificació
La hiperpotassèmia és una alteració electrolítica causada principalment per una insuficiència en l’excreció urinària de potassi per malaltia renal crònica (ERC), però també per alteracions o ús de fàrmacs que afecten el sistema renina-angioensina-aldosterona (SRAA). També pot aparèixer en casos de cetoacidosi diabètica o estat hiperglucèmic hiperosmolar.
La hiperpotassèmia es defineix com a concentració sèrica de potassi >5,5 mmol/L i es considera com lleu si el potassi sèric és 5,5-5,9 mmol/L, moderada si 6,0-6,4 mmol/L o greu >6,5 mmol/L.
S?han autoritzat dos nous fàrmacs per al tractament de la hiperpotassèmia en adults, destinats principalment per al tractament de la hiperpotassèmia crònica lleu o moderada en pacients amb malaltia renal crònica (MRC) o amb tractament amb inhibidors del SRAA. El tractament habitual en aquests casos es basa en la modificació de la dieta, l?ús de diürètics, el tractament de l’acidosi metabòlica crònica, evitar l’ús d’antiinflamatoris no esteroïdals o el tractament amb resines d’intercanvi catiònic (poliestirè sulfonat de sodi i calci).
Objectiu
Es plantegen dos estudis, un per avaluar la incidència d?hiperpotassèmia (estudi d?indicació-prescripció) i un altre per descriure la població tractada amb resines d?intercanvi catiònic (estudi de prescripció-indicació).

Els objectius dels estudis són per una banda descriure les indicacions per les quals es prescriu ivabradina i per l?altra descriure els tractaments utilitzats en la població amb insuficiència cardíaca i sí aquests tractaments s?utilitzen en les situacions clíniques adequades

En las últimas décadas la estimación a nivel mundial es que un 10-20% de la población pediátrica está afectada por problemas mentales, encontrándose en los países occidentales el Trastorno de Déficit de Atención e Hiperactividad (TDAH), seguido de la depresión y la ansiedad como los trastornos más prevalentes[1][2].
El consumo de medicación psicotrópica ha aumentado en población pediátrica en los últimos años (niños y adolescentes, <18años) en Europa[3][4][5]. Sin embargo, durante esta etapa de la vida los facultativos se encuentran en ocasiones con falta de fármacos autorizados para estos grupos de edad, por falta de evidencia de seguridad y eficacia durante el desarrollo de los fármacos al no incluirse estos grupos de la población en los ensayos clínicos, así como falta de formulaciones adaptadas a ladosificación en pediatría[6]. Si bien existe una gran variación a nivel internacional en el consumo de medicación psicotrópica en población pediátrica, este hecho podría estar relacionado e influenciado por múltiples factores, desde factores nosológicos como la cultura de cada país frente a las enfermedades mentales, sin olvidar las tendencias en la práctica clínica, los sistemas de salud y la política de sanidad[7][8]. En estas últimas dos décadas se han realizado en varios países (Reino Unido, Alemania, Francia, Italia, Dinamarca) estudios de patrón de consumo de fármacos psicotrópicos en población infantil [9][10][11][12][13]. En España no hemos encontrado ningún estudio publicado sobre la utilización de psicofármacos en pediatría, motivo por el cual el equipo investigador está realizando un estudio (Estudio PEPSICAT) de uso de medicación psicotrópica en niños y adolescentes en Cataluña durante la última década, con datos procedentes de la historia electrónica de atención primaria (SIDIAP) [14]. SIDIAP (Sistema de Información para el desarrollo de la Investigación en Atención Primaria) es una base de datos que contiene información clínica anonimizada procedente de eCAP, programa de historia clínica electrónica de atención primaria, y que cubre aproximadamente el 80% de la población catalana. Según datos internos de un estudio pendiente de publicar, el 34,5% de los pacientes tratados con fármacos psicoestimulantes en la última década (2007-2017) no tenían un registro diagnóstico asociado. Este hecho nos ha llevado a proponer el actual trabajo de campo englobado en el estudio PEPSICAT, para conocer y analizar los diagnósticos registrados en las historias clínicas de atención primaria de los pacientes menores de edad iniciadores de psicofármacos, y también los posibles motivos de falta de registro diagnóstico.

Irritable bowel syndrome (IBS) is a chronic, relapsing gastrointestinal condition characterised by abdominal pain, bloating, and changes in bowel habits. Prevalence estimations vary with the diagnostic criteria used, and in the United Kingdom (UK) were estimated between 9.5% and 22%. IBS can be classified according to Rome III criteria on the basis of the stool?s characteristics: IBS predominantly with diarrhoea (IBS-D); IBS predominantly with constipation (IBS-C); and IBS with mixed bowel habits (IBS-M), with approximately one third of IBS patients having each type. Retrospective cohort (patients newly prescribed linaclotide). The specific research objectives for this study are to: 1) Describe the characteristics of patients prescribed linaclotide at time of first prescription, overall and by specific subgroups of interest; 2) Describe the extend of linaclotide off-label use; 3) Describe the proportion and characteristics of patients prescribed linaclotide (overall, and by alleged indication [IBS-C vs. other indications] who experience discontinuation of linaclotide or switching from linaclotide to other drugs potentially used by patients with IBS-C; 4) Describe the duration of linaclotide treatment until discontinuation or switching. All analyses will be first performed separately in each of the study countries. In addition, for the primary study objectives, aggregated analyses with data from all three countries will be performed.