NOTA PEL COMITÈ CIENTÍFIC DEL SIDIAP:
Aquest és una estudi requerit per la EMA de forma urgent (els resultats s’han de presentar a la EMA a finals d’agost). Els investigadors/es de l’estudi són conscients que les dades de suicidi no estàn disponibles al SIDIAP, però si les dades d’ansietat i depressió, així com d’altres outcomes relacionats amb suicidi com ara “self-harm” o “suicide attempt”.

Rationale and background
There have been reports on a potential association between use of doxycycline and suicide. By means of a self-controlled case series and an active comparator study, the study aims to assess the association between use of doxycycline and specific outcomes of interest (i.e. suicidality events).
Research questions
1. Is there a causal association between the use of doxycycline and suicide-related events?
2. Does the association between doxycycline use and completed suicide and suicide-related events vary by indication of use, compared to active comparators?
Objectives
1. To use a self-controlled case series study to assess the association between use of doxycycline and composite suicide events (including suicide ideation, suicide attempt, self-harm), and composite outcome of depression/anxiety.
2. To use a new-use cohort study to assess the association between doxycycline and completed suicide, composite suicide-related events (suicide ideation, suicide attempt, self-harm), composite suicide-related events (completed suicide, suicide ideation and suicide attempt, self-harm), and composite outcome of depression/anxiety, compared to active comparators, stratified by indication of acne vulgaris, rosacea, chlamydia and lower respiratory tract infection (CAP or bronchitis)
Research methods
Study design
Self-controlled case series (objective 1) and new-user cohort study with active comparator (objective 2).
Population
The study population is new users of doxycycline (SCCS and cohort study) or the comparators (cohort). The new-user cohorts will be per indication: acne vulgaris: doxycycline, erythromycin or isotretinoin; rosacea: doxycycline, erythromycin or isotretinoin; chlamydia: doxycycline, azithromycin, erythromycin or amoxicillin; and lower respiratory tract infection (CAP and bronchitis): doxycycline, azithromycin, or amoxicillin.
Variables
Condition of interest
Indications of interest are acne vulgaris, rosacea, chlamydia, and lower respiratory tract infection (community-acquired pneumonia and bronchitis).
Outcomes of interest are completed suicide (cohort study only), composite (completed suicide [cohort only], suicide ideation, suicide attempting and self-harm), and composite outcome of depression or anxiety.
Data sources
1. Integrated Primary Care Information (IPCI), Netherlands
2. The Information System for Research in Primary Care (SIDIAP), Spain
3. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
Sample size
In the SCCS to detect an IRR = 2.0 for the exposure-outcome association, the study size should be at least 245 persons. For an IRR = 1.5, the study size should include at least 828 persons. In the cohort study, with the assumption follow-up duration of 90-days and IRR = 2.0 for the exposure-outcome association (composite completed suicide, attempt, ideation or self-harm) the sample size should be at least 191,000 per group. To detect an IRR = 2.0 for the exposure-outcome association of depression/anxiety with the assumed follow-up duration of 90-days, the sample size should be at least 38,000 per exposure group.
Analytical methods
Incidence rates (IR) of the suicide-related events (suicide attempt, ideation and self-harm), depression or anxiety in people using doxycycline will be estimated and the association between doxycycline and the outcomes will be assessed using (adjusted) incidence rate ratios (IRR) in a self-controlled case series study, using the SelfControlledCaseSeries R package.
In a new-user cohort design using the CohortMethods R package, we will perform propensity-score matching of patients prescribed doxycycline to active comparators. This analysis will be conducted within cohorts of the different indication of use (acne, rosacea, chlamydia and LRTI) Cox-proportional hazards regression will estimate hazards ratios to assess the association of doxycycline with completed suicide in addition to the composite outcome of suicide-related events (suicide ideation, suicide attempt, self-harm) and the composite outcome of depression and anxiety.

Rationale and background
The Medicines Shortages SPOC Working Party (responsible for monitoring and reporting events that could affect the supply of medications in the EU) has been monitoring shortages of different medications to treat ADHD, mainly due to an increased demand in multiple markets, production constraints related to raw material availability, new regulatory approvals for some medications, and changes in the competitive landscape. The main products under monitoring are lisdexamfetamine and methylphenidate, but 3 more have the indication in Europe (Atomoxetine, dexamfetamine and guanfacine). Currently, the situation appears to be stable in the EU and there are no critical shortages. However, some constraints in the supply could arise throughout 2024.
To better anticipate potential shortages and its impact on appropriate patient management, it would be important to assess the evolution of prescriptions over time and get an overview of how these ADHD medications are used across Europe.
Research question and objectives
The overall aim of this study is to characterise the use of ADHD medications in the period of 2010 to 2023. The specific objectives are:
1. To estimate the monthly and yearly period prevalence of use of each ADHD medicine, overall and stratified by age and gender in each database.
2. To estimate the monthly, quarterly, and yearly incidence of use of each ADHD medicine, overall and stratified by age and gender in each database.
3. Among new users of each ADHD medicine, to identify the indication at the time of the initial of the prescribing/dispensing, overall and stratified by age, sex, and quarter.
4. Among new users of each ADHD medicine, to estimate the initial dose, cumulative dose, and time on treatment of the initial medication, overall and stratified by age, sex, indication at index, and quarter.
5. Among new users of any ADHD medicine, to estimate the total treatment duration, number of prescriptions overall and by medicine. Among new users of each ADHD medicine, to estimate the time from treatment initiation to first discontinuation, stratified by initial medicine and quarter of the year.
6. To identify the treatment pathway of each individual who initiated an ADHD medicine, including treatment add-on, switch and concurrent medication/co-prescribing, stratify by calendar time of initiation.
Methods
Study design
Population-level drug utilisation study (Objectives 1 and 2)
Patient-level utilisation study (Objectives 3 – 6, new user cohort study)
Population
In the population-level utilization of ADHD medications, all individuals aged 3 years and older, registered in the respective databases since 1st of January of 2010 to the latest available data, with at least 365 days of prior data availability, will be included.
In the patient-level utilization of ADHD medications, new users will be identified using the first record of any of the ADHD medications of interest within the study period, having no previous records for any study medication during the 12 months before cohort entry.
Variables
Drugs of interest: Five approved medications for the treatment of ADHD in Europe: methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine and guanfacine.
Data source
IQVIA LPD Belgium, covering a sample of outpatient records from Belgium
IQVIA DA Germany, covering a sample of outpatient records from Germany
IPCI, covering Dutch primary care
SIDIAP Database, covering Spanish primary care
BIFAP, covering Spanish primary care
CPRD, covering UK primary care
Statistical analysis
Objectives 1 to 2 are population-level drug utilisation study, monthly, (quarterly) and yearly period prevalence and incidence use of each ADHD medications will be estimated, overall and stratified by age group and sex.
Objectives 3 to 6 are patient-level drug utilisation study. In Objectives 3 and 4, new user cohorts will be constructed for each ADHD medicine with pre-defined washout period, indication for the initial prescribing/dispensing will be estimated, overall and stratified by age, sex, and quarter of the year. Initial dose, cumulative dose and length of the treatment will be calculated. In Objective 5 and 6, we will construct new user cohorts of any ADHD medicine, estimate the total treatment duration, number of prescriptions. Treatment pathway will be defined and proportion of individuals in each path and the length of each treatment stage will be reported.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as “<5”.

Rationale and background
Chronic skin conditions like acne and psoriasis cause significant physical and psychological distress, leading to social stigmatization and an increased risk of mental health issues, including depression and anxiety. Concerns about their link to suicidality-related events are rising. It has been discussed several signals of suicidal ideation associated with treatments for acne and/or other skin disorders. For these signals, it is difficult to estimate the extent of the confounding by indication as the underlying patient population is widely believed to be at increased risk of suicide related conditions. Despite this, there is insufficient data in the literature regarding the background rates of such outcomes in these populations and most studies focusing on broader mental health outcomes. This study aims to evaluate suicide-related drug safety signals associated with treatments for the conditions of acne and psoriasis. Understanding of the background rate of suicidality in patient with these conditions and the extent to which this differs from the general population will aid in the assessment of such signals.

Research questions
What are the background incidence rates of suicidality-related events (completed/attempted suicide, suicidal ideation, and intentional self-harm) in the general population and in patients with acne and psoriasis, overall and stratified by sex, age categories, and by calendar year? Results will further be stratified in individuals with and individuals without a medical history of mental health disorders at start of follow-up.

Objectives
1. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in patients with acne stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders.
2. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in patients with psoriasis stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders
3. What is the incidence rate of i) completed suicide, ii) attempted suicide, iii) suicide ideation, iv) intentional self-harm and v) composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm in the general population stratified by sex, age category (12-<18 years, 18-30, 31-40, 41-50 etc, >=81 years), calendar year and history of mental health disorders

Research methods

Study design
Population level cohort study

Population
The study population will include all individuals present in the database during the study period (2010 to 2023) and with at least one year of database history.
Within this population 2 sub-cohorts will be nested namely one on individuals newly diagnosed with acne and one consisting of individuals newly diagnosed with psoriasis.
Patients with a history of attempted suicide, suicide ideation and intentional self-harm will NOT be excluded from the study, but results will be provided, stratified by presence (or absence) of a medical history of mental health disorders prior to start of follow-up.

Outcomes
Outcomes of interest are i) completed suicide, ii) attempted suicide, iii) suicide ideation or iv) intentional self-harm and v) the composite endpoint of completed/attempted suicide, suicide ideation or intentional self-harm.

Variables
Sex, age, and calendar year.
Medical history of mental health disorders (i.e. anxiety, depression, bipolar disorder, post-traumatic stress disorder, eating disorders, and schizophrenia).

Data sources
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Integrated Primary Care Information (IPCI), Netherlands
3. The Information System for Research in Primary Care (SIDIAP), Spain
4. The Valencia Health System Integrated Database (VID), Spain
5. The National Public Health Information System (NAJS), Croatia

Sample size
No sample size has been calculated as this is a descriptive Disease Epidemiology Study where we are interested in the incidence rates of suicidality in patient with chronic skin conditions.

Analytical methods
For the calculation of the incidence rates of the outcomes of interest, the “IncidencePrevalence” R package will be used. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as “<5”. All analyses will be reported by country/database, overall and stratified by sex, age category and calendar year, when possible (minimum cell count reached). Incidence rates will be given together with 95% Poisson confidence intervals.

NOTA PEL COMITÈ CIENTÍFIC DEL SIDIAP:
Aquest és una estudi requerit per la EMA de forma urgent (els resultats s’han de presentar a la EMA a principis d’octtubre). Només podrem participar en aquest estudi si aconseguim aprovació dels comités com a molt tard a finals de setembre.

Rationale and background
Azathioprine is a purine analogue and prodrug of mercaptopurine that is used as an immunosuppressive medication alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation and to treat certain autoimmune diseases, where it is considered a steroid-sparing agent. The PRAC recently discussed a signal procedure regarding the association between treatment with azathioprine and non-cirrhotic portal hypertension/porto-sinusoidal vascular disease (PSVD).
Through this study we aim to characterize patients newly treated with azathioprine, to contextualize the signal assessment.
Research question and objectives
This is a study in incident users of azathioprine aiming to characterise new users of azathioprine with respect to indications for treatment, age at treatment initiation, and sex, and to summarise the treatment durations with azathioprine for all indications combined, and for each individual treatment indication.
Study specific objectives are as following:
1. Characterise azathioprine initiators by sex and age at first prescription
2. Identify potential indications for azathioprine, and the percentage of azathioprine-treated patients for each pre-defined approved indication:
a) Organ transplantation
b) Severe rheumatoid arthritis or chronic polyarthritis
c) Inflammatory bowel disease
d) Systemic lupus erythematosus
e) Dermatomyositis
f) Polyarteritis nodosa
g) Pemphigus vulgaris and bullous pemphigoid
h) Behçet’s disease
i) Refractory autoimmune haemolytic anaemia
j) Refractory idiopathic thrombocytopenic purpura
k) Polymyositis
l) Pyoderma gangrenosum
m) Multiple sclerosis
n) Myasthenia gravis
o) None of the above/missing
3. Estimate and summarise duration of treatment with azathioprine, overall, and stratified per indication
Methods
Study design
Patient-level drug utilisation study
Study period
01/01/2000 – 31/12/2023
Population
For this study we have one cohort, namely:
• Population of individuals newly treated with Azathioprine
Data source
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Integrated Primary Care Information (IPCI), Netherlands
3. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
4. Institut Municipal Assistència Sanitària Information System (IMASIS), Spain
5. The Information System for Research in Primary Care (SIDIAP), Spain
Sample size
Based on a preliminary feasibility assessment, the expected person counts for Azathioprine were 900 for IMASIS, 6,000 for IPCI, 23,700 for IQVIA DA Germany, 24,500 for SIDIAP and 52,100 for CPRD GOLD.
Exposure of interest
Azathioprine use.
Outcomes of interest
• Characteristics (sex and age)
• Indication
o Organ transplantation
o Severe rheumatoid arthritis or chronic polyarthritis
o Inflammatory bowel diseases
o Autoimmune hepatitis
o Systemic lupus erythematosus
o Dermatomyositis
o Polyarteritis nodosa
o Pemphigus vulgaris and bullous pemphigoid
o Behcet’s disease
o Refractory autoimmune haemolytic anaemia
o Refractory idiopathic thrombocytopenic purpura
o Polymyositis
o Pyoderma gangrenosum
o Multiple sclerosis
o Myasthenia gravis
• Treatment duration, overall and by indication

Statistical analysis
Characterisation of individuals newly initiating treatment with Azathioprine will be done using the CohortCharacteristics and CohortDiagnostics R packages. For the second and third objective, we will use the DrugUtilisation package to characterise Azathioprine use including counts (%) for each indication, and treatment duration.

Rationale and background
Antipsychotic drugs have been associated with several adverse drug reactions, particularly in the elderly. Somnolence, hypotension, extrapyramidal side effects and gait abnormalities are well-recognized side effects that may in turn contribute to the risk of falls and fracture in elderly persons (1). Similarly, cardiovascular adverse effects, falls and injuries may increase mortality.
Antipsychotic drugs are indicated for the management of schizophrenia and bipolar disorder. Antipsychotics are also used to manage behavioural and psychological symptoms of dementia (BPSD) and recommendations over their use suggest they should be discontinued after BPSD symptoms resolve. Safety concerns have previously led to regulatory warnings and risk communications over their use (2,3).
Antipsychotic drugs can be classified into typical and atypical antipsychotics with different recommendations for their use. For example, guidelines recommend the preferential use of atypical antipsychotics when required for the management of BPSD (4).
The rationale of the study is to provide an overview of common antipsychotic prescribing in Europe, and to describe the characteristics of patients initiating antipsychotics. This may help to contextualize information contained in future antipsychotic periodic safety update reports.
Research question and objectives
1. To characterise older people with first use of common antipsychotics in terms of age, gender and indication/comorbidities.
2. To measure trends in the incidence of first use of common antipsychotic prescribing in older people overall, by typical/atypical grouping and by top 5 most common drug substances per database. Results will be stratified by database, calendar year, age and sex.
3. To characterise first time users of common antipsychotic drug therapy in older people after initiation by drug substance (in terms of initial dose and duration).
4. To measure survival in older people with first use of common antipsychotic overall, for typical/atypical grouping and for top 5 most common drug substances per database.
Methods
Study design
• New user cohort study (Objective 1 and 4, Patient-level antipsychotic utilisation)
• Population level cohort study (Objective 2, Population-level antipsychotic utilisation)
• New user cohort study (Objective 3, Patient-level characterisation)
Population
Population-level utilisation of antipsychotic drugs: All individuals aged = 60 years old between 01/01/2017 and 31/12/2023, with at least 365 days of prior history before the day they become eligible for study inclusion. For incidence, anyone with prior use of antipsychotic/s of interest will be excluded from the analysis.
Patient-level antipsychotic drug utilisation and patient-level characterisation: New users of antipsychotic drugs in the period between 01/01/2017 and 31/12/2023 (or latest date available), with at least 365 days of visibility prior to the date of their first antipsychotic prescription and no prior use of the respective antipsychotic drug/s.
Variables
Drugs of interest: Sulpiride, Quetiapine, Risperidone, Olanzapine, Haloperidol, Aripiprazole, Piamperone, Prothipendyl, Prochlorperazine, Chlorprothixene, Promazine, Paliperidone, Zuclopenthixol, Clozapine, Fluspirilene, Amisulpride, Fluphenazine, Perphenazine, Pimozide, and Ziprasidone
Data sources
• SIDIAP (Spain, Primary Care Database) [Objective 1 to 4]
• IPCI (Netherlands, Primary Care Database) [Objective 1 to 4]
• DK-DHR (Denmark, National Registry) [Objective 1 to 4]
• IQVIA DA Germany (Primary and Secondary care database) [Objective 1 to 3]
• IQVIA LPD Belgium (Primary and Secondary care database) [Objective 1 to 3]
• NAJS Croatia (Croatia, National Registry) [Objective 1 and 2]
Statistical analysis
Population-level drug utilisation, patient-level DUS, and patient-level characterisation will be conducted in databases based on data availability.
Population-level antipsychotic use: Annual antipsychotic use incidence rates per 100,000 person years will be estimated overall, by typical/atypical grouping and by top 5 individual drug substances per database. Results will be stratified by database, calendar year, age and sex.
Patient-level antipsychotic use: Patient-level characterization of new antipsychotic users will be conducted at index date, including patient demographics. Records of dementia, schizophrenia, bipolar disorder, depression and insomnia in the week/month or any time before antipsychotic initiation will be used as a proxy for indication and will be reported as proportions.
Initial and cumulative dose and treatment duration will be estimated for the first treatment era and the median [IQR] will be provided. Results will be stratified by drug route (restricting to antipsychotic with systemic routes).
Survival analyses using Kaplan-Meier curves for 1 year mortality will be conducted to estimate the probability of survival in new users of antipsychotic drugs overall, by typical/atypical grouping and by top 5 individual drug substances per database.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Rationale and background
Falls in older adults are associated with significant health outcomes, including hospitalization and increased mortality. Inappropriate prescribing, particularly in populations with multimorbidity and polypharmacy, is a recognized risk factor for falls. The prevalence of potentially inappropriate prescriptions, as outlined in Section K of the STOPP criteria, among individuals with recurrent falls remains uncertain across Europe.
Research question and objectives
What are the characteristics of patients with recurrent falls and how is STOPP Section K criteria prescribing implemented in Europe?
The study objectives are:
1.To characterise the cohort of individuals aged 65 years and older with recurrent falls in terms of age, gender, risk factors, comorbidities and concomitant prescriptions. Results will be stratified by database and where feasible by healthcare setting.
2.To estimate the overall survival of individuals aged 65 and older with recurrent falls.
3.To estimate prevalence of use of drug classes belonging to the STOPP section K criteria in individuals aged 65 and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. Results will be stratified by database, calendar year, age and sex.
4.To estimate incidence of use of drug classes belonging to the STOPP section K criteria in individuals aged 65 year and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. Results will be stratified by database, calendar year, age and sex.
5.To characterise a cohort of individuals aged 65 years and older with recurrent falls at time of their new prescription of any of the drug classes belonging to the STOPP section K criteria in terms of age, sex, comorbidities and comedication. Additionally, the proportion of individual drug substances within each drug class belonging to the STOPP section K criteria will be provided. Results will be stratified by database.
6.To determine the median duration of use the different drug classes belonging to the STOPP section K criteria at time of treatment initiation of drugs of interest in the individuals aged 65 and older, categorised into two cohorts: those with recurrent falls and those without recurrent falls. To provide product names with details on strength, formulation and volume.
Methods
Study design
Cohort analysis (Objective 1 and 2, Patient level characterisation of individuals aged 65 and older with recurrent falls in terms of age, sex, risk factors, comorbidities and concomitant medication and survival).
Population-level cohort study (Objective 3 and 4, Population-level drug utilization of drug classes belonging to the STOPP section K criteria in individuals aged 65 and older, categorised into those with recurrent falls and those without recurrent falls).
New drug user cohort study (Objective 5 and 6, Patient-level drug utilization of drug classes belonging to the STOPP section K criteria with regard to summary characterization (age, sex, comorbidities and comedication) and proportion of the individual drugs in individuals aged 65 and older with recurrent falls and duration of treatment in patients aged 65 and older, categorised into those with recurrent falls and those without recurrent falls).
Population
Patient-level characterisation: Patient-level characterisation will include individuals aged 65 years and older with a diagnosis of recurrent falls registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior to the date of recurrent fall diagnosis (index date). Additional eligibility criteria, a minimum of 1 year of potential follow-up after index date, will be applied for survival analysis.
Population-level utilisation of drug classes belonging to the STOPP section K criteria: Population-level drug utilisation analyses will include individuals aged 65 and older registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior becoming eligible for study inclusion. Categorisation will be done on those with recurrent falls and those without recurrent falls.
Patient-level utilisation of drug classes belonging to the STOPP section K criteria: Patient-level utilisation will include new users of drug classes belonging to STOPP section K criteria in a cohort of individuals aged 65 years and older with recurrent falls registered in the respective databases between 1st of January 2013 and 31st of December 2023, with at least 1 year of data visibility prior becoming eligible for study inclusion and no use of the respective drug classes belonging to the STOPP section K criteria in the previous 1 year prior to the index date. Product names with details on strength, formulation and volume will also be reported.
Variables
Drug classes listed in STOPP section K criteria: Benzodiazepines, Antipsychotics, Vasodilating drugs (nitrates, ACE inhibitors, ARB inhibitors, calcium channel blockers), Hypnotic z-drugs, Anti-epileptics , First generation antihistamines, Opioids, Antidepressants, Alpha-blockers, Centrally acting antihipertensives, Antimuscarinic drugs (indicated for overactive bladder)
Conditions of interest: Recurrent falls
Data sources
Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
Finnish Care Register for Health Care (FinOMOP-HILMO), Finland
Croatian National Public Health Information System (NAJS), Croatia
The Information System for Research in Primary Care (SIDIAP), Spain
Statistical analysis
Patient-level characterisation: Patient-level characterisation including age, sex, comorbidities and comedication will be conducted at the date of diagnosis of recurrent falls. Comorbidities and comedication will be assessed at index date and 1 year prior to the index date. (Objective 1)
Overall survival (Objective 2) will be calculated using data on time at risk of death from any cause and the Kaplan-Meier method. Results will be reported as plots of the estimated survival curves as well as the estimated probability of survival at years 1, 3, and 5. This analysis will be conducted only for databases that collect systematically data on mortality.
Statistical analyses will be conducted using the “CohortCharacteristics”, “PatientProfiles” and “CohortSurvival”” R packages.
Population-level utilisation of drug classes belonging to the STOPP section K criteria: Annual incidence rates (expressed as number of new users per 1,000 person-years) and annual period prevalence of the use of drug classes belonging to the STOPP section K criteria will be estimated in individuals aged 65 and older,
categorised into those with recurrent falls and those without recurrent falls (objective 3 and 4). The statistical analysis will be performed based on OMOP-CDM mapped data using “IncidencePrevalence” R package. The results will also be stratified by database, calendar year, age and sex.
Patient-level utilisation of drug classes belonging to the STOPP section K criteria: Characterisation including age, sex, comorbidities and comedication will be conducted at the date of new (incident) prescription of drug classes belonging to the STOPP section K criteria for individuals aged 65 years and older with diagnosis of recurrent falls (index date). Frequency of comorbidities and comedication will be assessed at index date and in 1 year prior to the to the index date. Additionally, proportion of individual drug substances within each drug class belonging to the STOPP section K criteria will also be provided. Duration of treatment with drug classes belonging to the STOPP section K criteria will be calculated and summarized, providing minimum, quartiles and maximum for those with recurrent falls and those without recurrent falls. Statistical analyses will be conducted using the “CohortCharacteristics”, “PatientProfiles” and “DrugUtilisation” R packages based on OMOP-CDM mapped data.
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background
Antipsychotic drugs have been associated with several adverse drug reactions, particularly in the elderly. Somnolence, hypotension, extrapyramidal side effects and gait abnormalities are well-recognised side effects that may in turn contribute to the risk of falls and fracture in elderly persons (1). Similarly, cardiovascular adverse effects, falls and injuries may increase mortality.
Antipsychotic drugs are indicated for the management of schizophrenia and bipolar disorder. Antipsychotics are also used to manage behavioural and psychological symptoms of dementia (BPSD) and recommendations over their use suggest they should be discontinued after BPSD symptoms resolve. Safety concerns have previously led to regulatory warnings and risk communications over their use (2,3).
Antipsychotic drugs can be classified into typical and atypical antipsychotics with different recommendations for their use. For example, guidelines recommend the preferential use of atypical antipsychotics when required for the management of BPSD (4).
The rationale of the study is to provide an overview of common antipsychotic prescribing in Europe among people with dementia, and to describe the characteristics of patients initiating antipsychotics. This may help to contextualize information contained in future antipsychotic periodic safety update reports.
Research question and objectives
1.
To characterise people with dementia with first use of common antipsychotics in terms of age, gender, indication and comorbidities.
2.
To measure trends in the incidence of first use of common antipsychotic prescribing overall, by typical/atypical grouping and by top 20 most common drug substances. Results will be stratified by database, calendar year, age and sex.
3.
To characterise first time users of common antipsychotic drug therapy after initiation in people with dementia by drug substance (in terms of initial dose and duration).
4.
To measure overall survival in people with dementia with first use of common antipsychotic overall, for typical/atypical grouping and for top 20 most common drug substances.
Methods
Study design
•
New user cohort study (Objective 1 and 4, Patient-level antipsychotic utilisation)
•
Population level cohort study (Objective 2, Population-level antipsychotic drug utilisation)
MODEL DE SOL·LICITUD
2 IMP-126-CT Versió 07
•
New user cohort study (Objective 3, Patient-level characterisation)
Population
Population-level antipsychotic utilisation: All individuals between 01/01/2013 and 31/12/2023, with a diagnosis of dementia and at least 365 days of prior history before the day they become eligible for study inclusion. For incidence, anyone with prior use of antipsychotic/s of interest will be excluded from the analysis.
Patient-level antipsychotic drug utilisation and patient-level characterisation: New users of antipsychotic drugs in the period between 01/01/2013 and 31/12/2023 (or latest date available), with at least 365 days of visibility prior to the date of their first antipsychotic prescription, a prior diagnosis of the condition of dementia and no prior use of the respective antipsychotic drug/s.
Variables
Drugs of interest: Sulpiride, Quetiapine, Risperidone, Olanzapine, Haloperidol, Aripiprazole, Piamperone, Prothipendyl, Prochlorperazine, Chlorprothixene, Promazine, Paliperidone, Zuclopenthixol, Clozapine, Fluspirilene, Amisulpride, Fluphenazine, Perphenazine, Pimozide, and Ziprasidone
Data sources
•
SIDIAP (Spain, Primary Care Database) [Objective 1 to 4]
•
IPCI (Netherlands, Primary Care Database) [Objective 1 to 4]
•
DK-DHR (Denmark, National Registry) [Objective 1 to 4]
•
IQVIA DA Germany (Primary and Secondary care database) [Objective 1 to 3]
•
IQVIA LPD Belgium (Primary and Secondary care database) [Objective 1 to 3]
•
NAJS Croatia (Croatia, National Registry) [Objective 1 and 2]
Statistical analysis
Population-level antipsychotic utilisation, patient-level antipsychotic drug utilisation, and patient-level characterisation will be conducted in databases based on data availability.
Population-level antipsychotic utilisation: Annual antipsychotic use incidence rates per 100,000 person years will be estimated overall, by typical/atypical grouping and by top 20 individual drug substances. Results will be stratified by database, calendar year, age and sex.
Patient-level antipsychotic use: Patient-level characterization of new antipsychotic users will be conducted at index date (date of first prescription of the antipsychotic of interest), including patient demographics. Records of schizophrenia, bipolar disorder, depression and insomnia in the week/month or any time before antipsychotic initiation will be used as a proxy for indication and will be reported as proportions.
Initial and cumulative dose and treatment duration will be estimated for the first treatment era and the median [IQR] will be provided. Results will be stratified by drug route (restricting to antipsychotic with systemic routes).
Survival analyses using Kaplan-Meier curves for 1 year mortality will be conducted to estimate the probability of overall survival in new users of antipsychotic drugs overall, by typical/atypical grouping and by top 20 individual drug substances.
For all analyses a minimum cell counts of 5 will be used when reporting results, with any smaller counts will be noted as <5.

Mental disorders are increasing in the last years, in particular after COVID-19 pandemic, but its prevalence and incidence is still not quantified in particular subgroups of population and comparing different countries. We aim to investigate time trends of mental disorders from 2006 to 2024 using large real-world data. We propose to conduct a descriptive study on the prevalence and incidence of common mental problems (i.e. anxiety and depression), severe mental disorders (i.e. schizophrenia and bipolar disorder) and other mental conditions, such as self-harm, sleep disorders, developmental disorders, substance abuse and eating disorders among people of all ages. Using a network of large real-world data sources of primary healthcare, we aim to determine whether the long-term trends of prevalence and incidence of several mental problems remain stable over the time.
We will conduct a population-based cohort study to investigate the temporal trends of several mental conditions and whether the patterns vary according to sex, age groups, socioeconomic deprivation, and nationality. We will calculate the prevalence and incidence rates of diagnoses, prescriptions, and sick leaves/absences due to above-mentioned mental illnesses. The present study will be conducted in multiple databases in the Observational Health Data Sciences and Informatics (OHDSI) network willing to participate, including the Information System for Research in Primary Care (SIDIAP) which contains primary care records for approximately 6 million people in Catalonia, Spain.
Our study will enable to identify temporal trends in mental disorders in Catalonia, and potentially other countries, and will inform preventive strategies targeted to specific groups that are more vulnerable, helping to address mental health disparities across different demographics.

Rationale and background
Salbutamol is essential for managing asthma and chronic obstructive pulmonary disease (COPD) due to its rapid bronchodilation effects. The rising prevalence of these conditions in Europe, driven by aging populations and worsening air quality, has led to increased demand for salbutamol, especially in urban areas. A shortage would severely impact patient care, leading to challenges in managing acute symptoms and increased strain on alternative therapies, which are not as effective for immediate relief.
The aim of the study is to understand if salbutamol (inhaled formulation) use has been increasing over the last few years in Europe which will in turn inform a potential risk of shortage. And secondly to understand the impact of the shortage of salbutamol inhaled formulations on therapeutic alternative inhalation products. This exercise falls under preparedness and prevention activities.
Research question
What is the real-world use of salbutamol (inhaled formulations)?
Objectives
The aim of this study is to determine the real-world use of salbutamol (inhaled formulations).
The specific objectives of this study are:
1. To describe the overall (i.e. all drug formulations combined) rate of prescribing inhaled salbutamol (irrespective of type of formulation) by calendar time (month, year). Monthly prescribing rates will be provided by database and healthcare setting (inpatient/outpatient).
2. To describe the rate of prescribing inhaled salbutamol by type of formulation and calendar time (year, month). Monthly prescribing rates will be provided by database and healthcare setting.
3. To describe the rate of prescribing other inhaled alternatives and oral salbutamol by calendar time (month, year). Monthly prescribing rates will be provided by database and healthcare setting.
4. To describe characteristics of individuals treated with inhaled salbutamol in terms of indication of use, sex and age (in age categories) stratified by formulation and provided by database and healthcare setting.
Methods
Study design
• Population level cohort study (Population-level drug utilisation analyses to objectives 1, 2, 3)
• New drug user cohort study (Patient-level drug utilization analyses to objective 4).
Population
The study population will include all patients presents in the databases and users of medication with inhaled salbutamol and other inhaled alternatives prescribing in the period between 01/01/2015 to the end of available data. For this population, rates of prescribing inhaled salbutamol and other inhaled alternatives and the indication for use of inhaled salbutamol will be explored. Patients need to have at least 365 days of data visibility prior to index date.
Variables
Therapeutic drug class of interest as exposures (all inhaled formulations):
Salbutamol (dry powder, pressurized metered dose inhaler, solution for inhalation), terbutaline, fenoterol, ipratropium bromide, oxitropium bromide, salbutamol + ipratropium, formoterol/budesonide, oral salbutamol
Conditions of interest: Asthma, COPD and emphysema, respiratory conditions due to inhalation of chemical substances, bronchitis, bronchospasm.
Relevant covariates: Sex, age, calendar months and years
Data source
1. Clinical Practice Research Datalink (CPRD) GOLD, United Kingdom
2. Danish Data Health Registries (DK-DHR), Denmark
3. Institut Municipal Assistència Sanitària Information System (IMASIS), Spain
4. Integrated Primary Care Information (IPCI), Netherlands
5. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
6. Croatian National Public Health Information System (NAJS), Croatia
7. The Information System for Research on Primary Care (SIDIAP), Spain
Sample size
No sample size has been calculated for this drug utilisation study, as our primary focus is to determine the prescribing rate of drug utilization of inhaled salbutamol products and other inhaled alternative in each database, irrespective of the sample size. Based on a preliminary feasibility assessment, the expected number of persons counts for medication with inhaled salbutamol in the databases included in this study ranged from 36,000 (IMASIS) to 3,154,200 (CPRD GOLD).
Statistical analysis
Population level drug utilisation: Monthly and yearly prescription rates of inhaled salbutamol and other inhaled alternatives (both treatment initiation and ongoing treatment episode) per 100,000 person-years will be estimated, overall and stratified by database and healthcare setting.
Patient level drug utilisation: Patient-level drug utilisation analyses will include describing the distribution of predefined indication of inhaled salbutamol use, stratified by i) type of formulation, ii) sex and iii) pre-defined age group at index date. Index date will be the date of first prescribing of salbutamol (irrespective whether incident or prevalent) during the study period.
The statistical analyses will be performed based on OMOP-CDM mapped data using “DrugUtilization” R package. A minimum cell counts of 5 will be used when reporting results, with any smaller count reported as <5.

Rationale and background
Portal vein thrombosis (PVT) stands as a significant and frequent complication among patients with cirrhosis, marking a critical event in their natural history. There is no approved treatment to prevent PVT in cirrhosis. Simvastatin is a statin with a lipophilic nature with a safety profile in cirrhosis. In vitro, treatment with simvastatin demonstrated a potential preventive role in endothelial-to-mesenchymal transition (EndMT) initiation and progression. We hypothesize that statins may offer a novel approach to preventing PVT development in individuals with cirrhosis.
Research questions
1.Are people with cirrhosis receiving statins different to individuals with cirrhosis not receiving statins?
2.In people with cirrhosis, initiating a treatment with statins reduces the risk of having PVT compared to not initiating a treatment with statins?
3.Does this effect differ according to the NASH and decompensation status of the cirrhosis?
Objectives
Main objective: Investigate whether statins can prevent PVT development in patients with cirrhosis in a large population in Catalonia from 2010 to 2023.
Specific objectives:
1.To describe and compare the characteristics of patients with cirrhosis with and without initiation of statin treatment in terms of age, sex, lifestyle factors, socioeconomic status, comorbidities, cirrhosis etiology, and stage of liver disease.
2.To investigate whether patients with cirrhosis initiating statins treatment have a lower risk of venous thrombosis and PVT compared to cirrhotic patients without statins treatment.
3 .To explore how statin initiation affects the risk of venous thrombosis and PVT in cirrhotic patients, comparing outcomes between those with NASH-related versus non-NASH cirrhosis, and between patients with compensated versus decompensated cirrhosis.
Research methods
Study design
A new-user matched cohort study, using individual-level routinely collected Electronic Health Records (EHR) from the SIDIAP database, from January 2010-December 2023.
Population
We will include all patients diagnosed with cirrhosis defined by ICD-10-CM diagnosis codes.
Variables
Drug of interest
The primary exposure of interest will be treatment with statins in patients with cirrhosis.
Condition of interest
The primary outcome of the study will be the incidence of venous thrombosis or PVT.
Analytical methods
In a new-user cohort design, we will perform propensity-score matching of cirrhotic individuals initiating a treatment with statins to cirrhotic individuals non-initiating a treatment with statins. Cox-proportional hazards regression will estimate hazards ratios to assess the association of statins with venous thrombosis and PVT. We will further explore whether this association is modified by cirrhosis etiology (NASH versus non-NASH) and stage of liver disease (compensated versus decompensated).