UMIN-CTR Clinical Trial

Basic information
Public title	Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Anticonvulsants in Japan
Acronym	Risk of SJS/TEN Associated with Anticonvulsants in Japan
Scientific Title	Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Anticonvulsants in Japan
Scientific Title:Acronym	Risk of SJS/TEN Associated with Anticonvulsants in Japan
Region	Japan

Condition
Condition	Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN)
Classification by specialty	Dermatology
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	The aim of this study is to assess the risk of SJS/TEN in new users of anticonvulsants.
Basic objectives2	Safety
Basic objectives -Others
Trial characteristics_1	Others
Trial characteristics_2	Others
Developmental phase	Not applicable

Assessment
Primary outcomes	Cohort study: Cumulative incidence of SJS/TEN Matched case-control study: Odds ratio for SJS/TEN
Key secondary outcomes

Base
Study type	Observational

Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms
Purpose of intervention
Type of intervention
Interventions/Control_1
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	Not applicable
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	Cohort study: Patients who meet the following criteria will be eligible for inclusion in this study: 1. Patients who were newly prescribed an anticonvulsant between April 1, 2012 to December 31, 2017 2. Patients who had an observational period of >90 days after initially being prescribed an anticonvulsant Matched case-control study: Patients who are identified by an algorithm and patients who are selected by risk-set sampling
Key exclusion criteria	Cohort study: None Matched case-control study: Patients who did not have an observational period of >180 days prior to the index date
Target sample size	5400000

Research contact person
Name of lead principal investigator	1st name Middle name Last name Hisashi Urushihara
Organization	Keio University
Division name	Division of Drug Development and Regulatory Science, Faculty of Pharmacy
Zip code
Address	1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512 Japan
TEL	03-5400-2649
Email	urushihara-hs@pha.keio.ac.jp

Public contact
Name of contact person	1st name Middle name Last name Hisashi Urushihara
Organization	Keio University
Division name	Division of Drug Development and Regulatory Science, Faculty of Pharmacy
Zip code
Address	1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512 Japan
TEL	03-5400-2649
Homepage URL
Email	urushihara-hs@pha.keio.ac.jp

Sponsor
Institute	Division of Drug Development and Regulatory Science, Faculty of Pharmacy, Keio University
Institute
Department

Funding Source
Organization	None
Organization
Division
Category of Funding Organization	Self funding
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization
Address
Tel
Email

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	Keio University

Other administrative information
Date of disclosure of the study information	2018 Year 11 Month 27 Day

Related information
URL releasing protocol	https://www.sciencedirect.com/science/article/pii/S1323893021000071
Publication of results	Published

Result
URL related to results and publications	https://www.sciencedirect.com/science/article/pii/S1323893021000071
Number of participants that the trial has enrolled	355
Results	There were increased odds of SJS/TEN in the new users of carbamazepine (OR 68.00, 95% confidence interval [CI] 8.49 to 8792.29) and lamotrigine (OR 36.00, 95% CI 3.84 to 4770.48). The ALDEN score was more than probable for 100% of cases exposed to lamotrigine or carbamazepine. The 90-day cumulative incidences of SJS/TEN per 100,000 new users were 93.83 for carbamazepine and 84.33 for lamotrigine. We found no significant elevated odds in the users of other anticonvulsants.
Results date posted	2021 Year 03 Month 23 Day
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics	A total of 71 SJS/TEN cases were identified, with 35 in males, and these were matched to 284 controls for the case-control substudy. Mean age at the index date for cases and controls combined was 45.4 years (SD, 13.5). Median follow-up period of the 71 SJS/TEN cases was 5.5 (interquartile range, 3.7 to 6.7) years. Compared with the controls, cases had more epilepsy (7.0% vs. 2.5%), anticonvulsant use (within 90 days before the index date, 18.3% vs. 1.4%).
Participant flow	Matched case-control study: Case We included patients who met the following criteria: 1) algorithm-positive, and 2) 180 days or more of active history in the JMDC claims database prior to the index date. Control For each case, four controls meeting the following criteria were randomly selected and matched through risk set sampling with replacement by sex, age at the date of medical encounter with an allowance of three years, and date of medical encounter (within three days' difference), in descending order of priority. Cohort Study: We established 33 individual cohorts of new users of a single anticonvulsant between April 1, 2012 and October 3, 2017. New users of an anticonvulsant were defined as having a preceding lookback period of at least 180 days without any prescription of the anticonvulsant of interest before the earliest record of anticonvulsant prescription in the study database, and were followed from the date of first prescription. To be eligible for analysis, new users were required to have a follow-up period of at least 90 days or to have developed SJS/TEN within 90 days after starting treatment with the anticonvulsant.
Adverse events	Not applicable because this is an epidemiological study using a claims database.
Outcome measures	We observed significantly increased odds ratios (ORs) for SJS/TEN among new users of carbamazepine (OR 68.00, 95% CI 8.49 to 8792.29) and lamotrigine (OR 36.00, 95% CI 3.84 to 4770.48) with ALDEN scores of "probable" or higher. The 90-day cumulative incidence of SJS/TEN per 100,000 new users was 93.83 (95% CI 46.92 to 187.63) for carbamazepine and 84.33 (95% CI 31.65 to 224.71) for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27 (95% CI 9.33 to 470.47). Cumulative incidence of SJS/TEN was 25.23 (95% CI 3.55 to 179.10) for levetiracetam, 7.52 (95% CI 1.06 to 53.40) for clonazepam, and 1.23 (95% CI 0.17 to 8.73) for diazepam, but their ALDEN scores were "very unlikely".
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Completed
Date of protocol fixation	2018 Year 04 Month 27 Day
Date of IRB	2018 Year 04 Month 27 Day
Anticipated trial start date	2012 Year 04 Month 01 Day
Last follow-up date	2017 Year 12 Month 31 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information	Study design: Cohort study, Matched case-control study Subjects: Patients who were registered in the Japan Medical Data Center (JMDC) Claims Database (April 1, 2012 through December 31, 2017) and satisfied the inclusion criteria

Management information
Registered date	2018 Year 11 Month 27 Day
Last modified on	2021 Year 03 Month 23 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039942