UMIN-CTR Clinical Trial

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

Stevens-Johnson syndrome (SJS)
Toxic epidermal necrolysis (TEN)

Classification by specialty

Dermatology

Classification by malignancy

Others

Genomic information

NO

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

Primary outcomes

Cohort study: Cumulative incidence of SJS/TEN
Matched case-control study: Odds ratio for SJS/TEN

Key secondary outcomes

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

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

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

Institute

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

Institute

Department

Personal name

Organization

None

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Keio University

Date of disclosure of the study information

2018

Year

11

Month

27

Day

URL releasing protocol

https://www.sciencedirect.com/science/article/pii/S1323893021000071

Publication of results

Published

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

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 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

Registered date

2018

Year

11

Month

27

Day

Last modified on

2021

Year

03

Month

23

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039942