Status: Finalised
First registered on:
16/01/2018
Last updated on:
24/03/2022
1. Study identification
EU PAS Register NumberEUPAS21769
Official titleRisk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus, Pimecrolimus, and Corticosteroids
Study title acronymJOELLE
Study typeObservational study
Brief description of the studyThe Protopic JOint European Longitudinal Lymphoma and skin cancer Evaluation (JOELLE) Study is a European, multinational cohort study to assess the risk of skin cancer and lymphoma in the pediatric and adult population treated with topical tacrolimus, pimecrolimus, and corticosteroids and in the untreated population.
The primary objective of the study is to estimate the incidence rate ratios of skin cancer and lymphoma in the pediatric and adult populations for new users of topical tacrolimus and topical pimecrolimus compared with users of moderate- to high-potency topical corticosteroids. Secondary objectives of the study are (1) to estimate the incidence rate ratios of skin cancer and lymphoma in users of moderate- to high-potency topical corticosteroids compared with persons not treated with topical tacrolimus, pimecrolimus, or corticosteroids and (2) to describe the patterns of use and the characteristics of users of topical tacrolimus, pimecrolimus, and corticosteroids.
Phase I of the study (EUPAS4357), involving the period 2002-2011, has been completed and the report was submitted to the EMA in December 2015. In the JOELLE Extension, the study has been extended for 4 additional years (2012-2015) in order to increase the number of exposed patients and the length of follow-up. Data beyond 2015 may be available in some databases and will be included in the analysis.
Was this study requested by a regulator?Yes: EMA
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
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?
No
Other centres where this study is being conducted
Multiple centres
In total how many centres are involved in this Study?5
Southern Denmark University, Denmark
Countries in which this study is being conducted
International study
Denmark
Netherlands
Sweden
United Kingdom
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed01/10/201728/09/2017
Start date of data collection15/11/201727/10/2017
Start date of data analysis
Date of interim report, if expected
Date of final study report30/09/201920/09/2019
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesLEO Pharma A/S100
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 1Av. Diagonal, 605, 9-1
Address line 2
Address line 3
CityBarcelona
Postcode08028
CountrySpain
Phone number (incl. country code)34933622805
Alternative phone number
Fax number (incl. country code)34937608507
Public Enquiries
Title Dr
Last name Arana
First name Alejandro
Address line 1Av. Diagonal, 605, 9-1
Address line 2
Address line 3
CityBarcelona
Postcode08028
CountrySpain
Phone number (incl. country code)34933622805
Alternative phone number
Fax number (incl. country code)34937608507
6. Study drug(s) information
Substance class (ATC Code)D11AH01 (tacrolimus)
Substance class (ATC Code)D11AH02 (pimecrolimus)
7. Medical conditions to be studied
Medical condition(s)Yes
Malignant melanoma
Neoplasm skin
Hodgkin's disease nodular sclerosis
Hodgkin's disease lymphocyte predominance type stage unspecified
Hodgkin's disease lymphocyte depletion type stage unspecified
Non-Hodgkin's lymphoma stage I
Non-Hodgkin's lymphoma stage II
Non-Hodgkin's lymphoma stage III
Non-Hodgkin's lymphoma stage IV
8. Population under study
Age
Children (2 - 11 years)
Adolescents (12 - 17 years)
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 subjects250000
Additional information
Tacrolimus: 150,000; Pimecrolimus: 100,000
10. Source of data
Is this study being carried out with an established data source?Yes
Data sources registered with ENCePP
Data sources not registered with ENCePP
Swedish National Health Databases, Sweden
Danish National Health Registries, Denmark
Sources of data
Disease/case registry
Administrative database, e.g. claims database
Routine primary care electronic patient registry
Pharmacy dispensing records
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 the study is to estimate the incidence rate ratios of skin cancer and lymphoma in the pediatric and adult populations for new users of topical tacrolimus and topical pimecrolimus compared with users of moderate- to high-potency topical corticosteroids diagnosed with atopic dermatitis.
Are there primary outcomes?Yes
Skin Malignancies: Malignant melanoma, Nonmelanoma skin cancer, Lymphomas: Cutaneous T cell lymphomas (CTCL), Hodgkin lymphomas (HL), Non Hodgkin lymphomas
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
Patients are followed-up from entry into each cohort (start date) until the earliest of occurrence of one of the following: first occurrence of any one of the study endpoints, death, disenrollment from the study databases, or end of the study period.
15. Data analysis plan
Please provide a brief summary of the analysis method
Incidence rates of each study malignancy will be estimated in users of topical tacrolimus, topical pimecrolimus, moderate- to high-potency topical corticosteroids, and in the general population. Incidence rate ratios and 95% CIs will be estimated comparing the rates between users of topical tacrolimus and topical pimecrolimus and users of moderate- to high-potency corticosteroids, and between users of moderate- to high-potency corticosteroids and the general population. Propensity scores will be used to match the study cohorts. Each research center will produce stratified data that will be analysed by the coordination center using standard stratified methods. The effect of cumulative dose and duration of use of topical tacrolimus and topical pimecrolimus will be estimated.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
Yes
17. Full protocol
18. Study Results
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
Arana A, Pottegård A, Kuiper JG, Booth H, Reutfors J, Calingaert B, Lund LC, Crellin E, Schmitt-Egenolf M, Kaye JA, Gembert K, Rothman KJ, Kieler H, Dedman D, Houben E, Gutiérrez L, Hallas J, Perez-Gutthann S. Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE). Clin Epidemiol. 2021;13:1141-1153
https://doi.org/10.2147/CLEP.S331287https://doi.org/10.2147/CLEP.S331287
Arana A, Pottegard A, Kuiper JG, Crellin E, Reutfors J, Schmitt-Egenolf M, Lund LC, Houben E, Booth H, Calingaert B, Kaye JA, Gembert K, Rothman KJ, Dedman D, Kieler H, Gutierrez L, Hallas J, Perez-Gutthann S. To what extent are topical tacrolimus or pimecrolimus associated with increased risk of skin cancer and lymphoma? Long-term results from Joelle Study. Poster presented at the 2020 36th ICPE International Virtual Conference on Pharmacoepidemiology & Therapeutic Risk Management; September 16, 2020.https://www.rtihs.org/sites/default/files/30560%20Arana%202020%20To%20what%20extent%20are%20topical%20tacrolimus%20or%20pimecrolimus%20associated%20with%20increased%20risk%20of%20skin%20cancer%20and%20lymphoma%20Long-term%20results%20from%20Joelle%20Study.pdf
Gutierrez L, Booth H, Dedman D, Crellin E, Kaye JA, Franzoni C, Arana A, Schmitt-Egenolf M, Sundstrom A, Bystrom C. Case validation of cutaneous lymphoma to minimize protopathic bias. Poster presented at the 35th Annual ICPE Conference; August 27, 2019. Philadelphia, PA. [abstract] Pharmacoepidemiol Drug Saf. 2019 Aug 20; 28(S2):645.https://www.rtihs.org/sites/default/files/29752%20Gutierrez%202019%20Case%20validation%20of%20cutaneous%20lymphoma%20to%20minimize%20protopathic%20bias.pdf
19. Other relevant documents
Other documents
DescriptionDocumentLatest version
