Status: Finalised
First registered on:
05/09/2017
Last updated on:
23/09/2021
1. Study identification
EU PAS Register NumberEUPAS20546
Official titleCohort Study of the Incidence of Major Cardiovascular Events in New Adult Users of Lisdexamfetamine and Remote Adult Users of Other ADHD Treatments
Study title acronym
Study typeObservational study
Brief description of the studyThis study will consist of multiple observational (non-interventional) population-based cohort studies of patients initiating Lisdexamfetamine dimesylate (LDX) compared with patients with remote use of other attention deficit and hyperactivity disorder (ADHD) medications, in three electronic health care data sources: the Danish National Registries, and the Swedish National Registers. The main objective of this study is to estimate the incidence rate (IR) and the adjusted incidence rate ratios (IRRs) of the composite major adverse cardiovascular events (MACE) endpoint in a cohort of adult patients who are current new users of LDX compared with a cohort of remote users of other ADHD treatments. Current use for LDX new users is defined as the duration of the LDX prescription or dispensing plus 30 days. The remote use of other ADHD treatments will be generated by selecting adult patients with at least one prescription/dispensing for a medication indicated for ADHD, other than LDX, during the 24 months prior to the index date and with no prescriptions or dispensings of these medications in at least the last 180 days before index date. The analysis will be conducted separately in each data source, and overall estimates of effect will be obtained using meta-analytic techniques as appropriate. The primary endpoint, MACE, will comprise the first occurrence of any of its individual components during follow-up: hospitalisation for acute myocardial infarction, fatal or non-fatal; hospitalisation for stroke, fatal or non-fatal; out-of-hospital coronary heart disease death; and out-of-hospital cerebrovascular death. Secondary endpoints are an extended MACE (EMACE) endpoint that includes hospitalisation for either unstable angina or TIA, the composite coronary and stroke components of EMACE, and an additional secondary endpoint that will be a composite of sudden cardiac death and serious ventricular arrhythmias.
Was this study requested by a regulator?Yes: EMA, Sweden
Is the study required by a Risk Management Plan (RMP)?
EU RMP category 2 (specific obligation of marketing authorisation)
Regulatory procedure number (RMP Category 1 and 2 studies only)
Other study registration identification numbers and URLs as applicable
2. Research centres and Investigator details
Coordinating study entity
Centre to which the investigator belongsRTI-HS
Department/Research groupPharmacoepidemiology & Risk Management
Organisation/affiliationRTI Health Solutions
Details of (Primary) lead investigator
Title Dr
Last name Rebordosa
First name Cristina
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Multiple centres
In total how many centres are involved in this Study?3
Countries in which this study is being conducted
International study
Denmark
Sweden
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed01/06/201701/06/2017
Start date of data collection01/12/201930/09/2019
Start date of data analysis
Date of interim report, if expected
Date of final study report30/06/202018/12/2020
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesShire Human Genetic Therapies, Inc., a wholly owned subsidiary of the Takeda Pharmaceutical Company Limited100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Dr
Last name Rebordosa
First name Cristina
Address line 1Av. Diagonal, 605, 9-1
Address line 2
Address line 3
CityBarcelona
Postcode08028
CountrySpain
Phone number (incl. country code)34933622807
Alternative phone number
Fax number (incl. country code)
Public Enquiries
Title Dr
Last name Rebordosa
First name Cristina
Address line 1Av. Diagonal, 605, 9-1
Address line 2
Address line 3
CityBarcelona
Postcode08028
CountrySpain
Phone number (incl. country code)34933622807
Alternative phone number
Fax number (incl. country code)
6. Study drug(s) information
Substance class (ATC Code)N06BA12 (lisdexamfetamine)
7. Medical conditions to be studied
Medical condition(s)Yes
Major Cardiovascular Events (MACE)
8. Population under study
Age
Adults (18 - 44 years)
Adults (45 - 64 years)
Adults (65 - 74 years)
Adults (75 years and over)
Sex
Male
Female
9. Number of subjects
Estimated total number of subjects170940
Additional information
7,800 person-years (p-y) of exposure to LDX are needed to exclude an IRR >3 with 80% probability, if the comparator cohort IR is 1/1,000 p-y. The estimated number of LDX patients needed are 37,986 for average duration of use of 75 days and 9,497 for 300 days. LDX patients will be matched 1:5 to remote users. The estimated number of patients will range from 56,982 (9,497*6) to 227,916 (37,986*6).
10. Source of data
Is this study being carried out with an established data source?Yes
Data sources registered with ENCePP
Sources of data
Disease/case registry
Routine primary care electronic patient registry
Pharmacy dispensing records
Hospital discharge data
11. Scope of the study
What is the scope of the study?
Risk assessment
Primary scope : Risk assessment
12. Main objective(s)
What is the main objective of the study?
The primary objective of this study is to estimate, in real-world settings, the incidence rate (IR) and the adjusted incidence rate ratios (IRRs) of the composite major adverse cardiovascular events (MACE) endpoint in a cohort of adult patients who are current new users of LDX compared with a cohort of remote users of other ADHD treatments in three European data sources.
Are there primary outcomes?Yes
Major cardiovascular events (MACE). MACE, will comprise hospitalisation for acute myocardial infarction (AMI), fatal or non-fatal; hospitalisation for stroke, fatal or non-fatal; out-of-hospital coronary heart disease death; and out-of-hospital cerebrovascular death.
Are there secondary outcomes?Yes
Extended MACE (EMACE). EMACE comprises all MACE components plus hospitalisation for either unstable angina or transient ischaemic attack (TIA), the composite coronary and stroke components of EMACE, and a composite of sudden cardiac death and serious ventricular arrhythmias.
13. Study design
What is the design of the study?
Cohort study
14. Follow-up of patients
Will patients be followed up?Yes
Please describe duration of follow up
For the primary analysis, follow-up will start at the index date and will end at the earliest of death, first occurrence of an outcome of interest, termination of enrolment in the health plan system, or end of study period.
15. Data analysis plan
Please provide a brief summary of the analysis method
Each research partner will conduct country-specific analyses within each data source to (1) select the study population; (2) describe the study cohorts, including patterns of demographics, medical history, exposures, and endpoints; (3) within its data, estimate exposure propensity scores that will be used to control for confounding; (4) create a summary of aggregated data set based on counts of patients, person-years, and outcome events according to the strata of age, sex and propensity scores; (5) analyse IR and standardised IRs; and (6) analyse crude and adjusted IRRs. IRs will be standardised to the distribution of person-time of LDX users by age, sex, quintiles of the propensity score, and data source. The coordinating centre activities include conducting a (1) pooled description analysis of study cohorts, (2) pooled analysis of IR and standardised IRs, and (3) pooled analysis of crude and adjusted IRRs. Mantel-Haenszel methods will be used to summarise IRRs across strata.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
No
17. Full protocol
18. Study Results
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
None
19. Other relevant documents
Conflict(s) of interest of
investigator(s)Not submitted
Composition of Steering Group and
ObserversNot submitted
Other documentsNot
submitted
Signed Code of
Conduct Checklist
Not submitted
Signed Code of Conduct Declaration
Not submitted
Signed Checklist for Study
Protocols
Not submitted
