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Status: Finalised First registered on: 09/01/2014

Last updated on: 10/11/2020

1. Study identification

EU PAS Register NumberEUPAS5529

Official titlePost-authorization safety program – validation of the Clinical Practice Research Datalink for the study of cardiovascular and neoplasm events in users of treatments for overactive bladder

Study title acronym

Study typeObservational study

Brief description of the studyMirabegron is a first in class therapeutic agent, with a mechanism of action distinct from that of antimuscarinic agents indicated for the treatment of overactive bladder (OAB). This is a retrospective cohort study of new users of individual antimuscarinic drugs: oxybutynin, tolterodine, darifenacin, solifenacin, trospium, and fesoterodine. The objectives are: to describe drug-use patterns, to calculate background rates of cardiovascular (CV) and cancer outcomes among antimuscarinic drug users and to validate outcome-specific case-identification algorithms based on electronic diagnosis codes in the Clinical Practice Research Datalink (CPRD) in the United Kingdom. Upon validation these algorithms will be used to evaluate CV and cancer risk associated with mirabegron as part of the required post-approval safety program to be implemented in the US and the EU. The study period is January 2004 through December 2012. The study will calculate incidence rates of the following endpoints: - CV: including acute myocardial infarction, stroke, all-cause mortality, CV mortality and a composite endpoint. - Neoplasm endpoint: including the 10 most commonly occurring in the general population. The data retrieved from primary care data, which contains prescriptions issued by the general practitioners (GP) and medical information recorded by GPs as part of their routine clinical practice, will be compared with information from other sources. The data are linkable, at least for a large subset of patients, with other health care data sets (e.g., hospitalization records, national mortality data, census data, cancer registry).

Was this study requested by a regulator?Yes: EMA, United States

Is the study required by a Risk Management Plan (RMP)? EU RMP category 3 (required)

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

Website/Homepagewww.rtihs.org

Details of (Primary) lead investigator

Title Dr

Last name Arana

First name Alejandro

Is this study being carried out with the collaboration of a research network?

Other centres where this study is being conducted

Not applicable (single centre)

Countries in which this study is being conducted

National study

United Kingdom

3. Study timelines: initial administrative steps, progress reports and final report

PlannedActual

Date when funding contract was signed05/04/201312/06/2013

Start date of data collection15/03/201431/03/2014

Start date of data analysis01/07/201427/08/2014

Date of interim report, if expected31/03/2015

Date of final study report28/08/201528/08/2015

4. Sources of funding

Please provide estimates of the percentage of funding by source for this study

Names(s)Approximate % funding

Pharmaceutical companiesAstellas Pharma Global Development, Inc.100

Charities

Government body

Research councils

EU funding scheme

5. Contact details for enquiries

Scientific Enquiries

Title Dr

Last name Arana

First name Alejandro

Address line 1Trav. Gracia, 56, Atico 1

Address line 2

Address line 3

CityBarcelona

Postcode08006

CountrySpain

Phone number (incl. country code)34933622805

Alternative phone number

Fax number (incl. country code)34934142610

Email address aarana@rti.org

Public Enquiries

Title Dr

Last name Arana

First name Alejandro

Address line 1Trav. Gracia, 56, Atico 1

Address line 2

Address line 3

CityBarcelona

Postcode08006

CountrySpain

Phone number (incl. country code)34933622805

Alternative phone number

Fax number (incl. country code)34934142610

Email address aarana@rti.org

11. Scope of the study

What is the scope of the study?

Validation of the CPRD database for the study of CV and neoplasm events in users of treatments for overactive bladder

Primary scope : Validation of the CPRD database for the study of CV and neoplasm events in users of treatments for overactive bladder

12. Main objective(s)

What is the main objective of the study?

Characterize users of OAB drugs. Describe patterns of usage of OAB drugs. Validate algorithms used for the diagnosis of study endpoints. Describe the availability of potential confounders in the CPRD, to help in the design of the PASS studies of mirabegron. Estimate IRs of study endpoints in new users of OAB drugs. Estimate the IRRs of CV outcomes in users of OAB drugs compared with tolterodine.

Are there primary outcomes?Yes

CV endpoints: AMI, stroke, CV mortality, all-cause mortality, major adverse cardiac events (MACE). Composite cancer endpoints: lung & bronchus, colon & rectum, melanoma of skin, urinary bladder, non-Hodgkin lymphoma, kidney & renal pelvis, pancreas, prostate (males), breast (females), corpus uteri (females).

Are there secondary outcomes?No

13. Study design

What is the design of the study?

Cohort study

Drug utilisation study

14. Follow-up of patients

Will patients be followed up?Yes

Please describe duration of follow up

For each subject, follow-up will start on the date of the first prescription for a drug of interest and will finish at the earliest of the following events: end of the study period, death, disenrollment from the database, occurrence of an excluded diagnosis, or occurrence of a study endpoint.

15. Data analysis plan

Please provide a brief summary of the analysis method

Summary statistics of the covariates will be generated. The characteristics of the users at cohort entry and the patterns of use of the study medications will be described. CV cases will be classified as definite, probable, possible or noncases after patient profile review.A random sample of definite, probable and noncases will be selected for validation. GPs will be asked to review patients’ medical records and charts and complete a questionnaire. Based on this assessment, the PPV will be calculated for the definite, probable and possible cases.The screening and validation method of neoplasm endpoints will depend on whether the medical practice where the study subject is enrolled consented to have its information linked to other health care data within the NHS system. Characteristics of subjects in practices without and with data linkage will be compared. The concordance between diagnosis derived from the CPRD, the Hospital Episodes Statistics and the cancer registry will be described

16. ENCePP seal

Are you requesting the ENCePP seal for this study? No

17. Full protocol

Document Latest version 178-CL-116 Validation Protocol_sigs-redacted.pdf 178-cl-116-clp-02-reissue-en-v3dot2_Redacted.pdf

18. Study Results

Document 178-cl-116-clrr-03-disc01-en-final-02_redacted2.pdf

Please list the 5 most relevant publications using data from your study

ReferenceLink to web-publication

Kaye JA, Margulis AV, Fortuny J, McQuay LJ, Plana E, Bartsch JL, Bui CL, Perez-Gutthann S, Arana A. Cancer Incidence after Initiation of Antimuscarinic Medications for Overactive Bladder in the United Kingdom: Evidence for Protopathic Bias. Pharmacotherapy 2017 Jun;37(6):673-83.http://onlinelibrary.wiley.com/doi/10.1002/phar.1932/epdf

Margulis AV, Fortuny J, Kaye JA, Calingaert B, Reynolds M, Plana E, et al. Validation of Cancer Cases Using Primary Care, Cancer Registry, and Hospitalization Data in the United Kingdom. Epidemiology. 2018;29(2):308-13.http://journals.lww.com/epidem/Abstract/publishahead/Validation_of_Cancer_Cases_Using_Primary_Care,.98768.aspx

Margulis AV, Fortuny J, Kaye JA, Calingaert B, Reynolds M, Plana E, McQuay LJ, Atsma WJ, Franks B, de Vogel S, Perez-Gutthann S, Arana A. Value of Free-text Comments for Validating Cancer Cases Using Primary-care Data in the United Kingdom. Epidemiology. 2018;29(5):e41-e2.https://journals.lww.com/epidem/Citation/publishahead/Value_of_Free_Text_Comments_for_Validating_Cancer.98703.aspx

Arana A, Margulis AV, McQuay LJ, Ziemiecki R, Bartsch J, Franks B, D´Silva M, Appenteng K, Varas C, Rothman KJ, Perez-Gutthann S. Variation in cardiovascular risk related to individual antimuscarinic drugs used to treat overactive bladder. A cohort study in the UK. Pharmacotherapy 2018 Mar;38(6):628-37.https://onlinelibrary.wiley.com/doi/abs/10.1002/phar.2121

Arana, A, Margulis, AV, Varas‐Lorenzo, C, et al. Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom. Pharmacoepidemiol Drug Saf. 2020; 1– 11.https://doi.org/10.1002/pds.5150

19. Other relevant documents

Conflict(s) of interest of investigator(s)Not submitted

Composition of Steering Group and ObserversNot submitted

1. Study identification

2. Research centres and Investigator details

Coordinating study entity

Details of (Primary) lead investigator

Is this study being carried out with the collaboration of a research network?

Other centres where this study is being conducted

Countries in which this study is being conducted

3. Study timelines: initial administrative steps, progress reports and final report

4. Sources of funding

Please provide estimates of the percentage of funding by source for this study

5. Contact details for enquiries

Scientific Enquiries

Public Enquiries

6. Study drug(s) information

7. Medical conditions to be studied

8. Population under study

9. Number of subjects

10. Source of data

11. Scope of the study

12. Main objective(s)

13. Study design

14. Follow-up of patients

15. Data analysis plan

16. ENCePP seal

17. Full protocol

18. Study Results

19. Other relevant documents