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HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions

Primary Purpose

Epilepsy, Neuropathy, Psychiatric Illness

Status
Unknown status
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
HLA screening before commencing aromatic AEDs
Sponsored by
Second Affiliated Hospital of Guangzhou Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Epilepsy focused on measuring HLA screening, SJS/TEN, MPE, AEDs

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Patients who are going to receive a kind of aromatic AEDs including CBZ, OXC, LTG, PHT, and PB as a new therapy. An AED was deemed newly commenced if there was no record of its prescription in at least the previous 12 months.
  2. Ethnic Han Chinese. None of the biological grandparents of the participants were from other races.

Exclusion Criteria:

  1. individuals who are not of Han Chinese descent.
  2. individuals who had undergone bone marrow transplantation

Sites / Locations

  • The Second Affiliated Hospital of Guangzhou Medical UniverstyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Group with two strong risk factors

Group with one strong risk factors

Group with one potential risk factors

Group without known risk factors

Arm Description

When HLA screening before commencing aromatic AEDs shows positive for both HLA-A*24:02 and HLA-B*15:02 in a patient, aromatic AEDs were not administrated for this patient.

When HLA screening before commencing aromatic AEDs shows positive for HLA-B*15:02, carbamazepine (CBZ) was not administrated, and other aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead. When HLA screening before commencing aromatic AEDs shows positive for HLA-B*15:01 or HLA-A*24:02, aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead.

When HLA screening before commencing aromatic AEDs shows positive for any potential risk allele such as HLA-B*15:11, HLA-A*02:01and HLA-DRB1*01:01, aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead.

When HLA screening before commencing aromatic AEDs shows negative for any known HLA risk allele , aromatic AEDs was administrated to these patients.

Outcomes

Primary Outcome Measures

AEDs-induced cADRs incidence
the incidence of AEDs-induced cADRs within the first 3 months of commencing an aromatic AED

Secondary Outcome Measures

Full Information

First Posted
June 9, 2017
Last Updated
September 2, 2018
Sponsor
Second Affiliated Hospital of Guangzhou Medical University
Collaborators
Guangzhou First People's Hospital, West China Hospital, Guangdong Provincial People's Hospital, First Affiliated Hospital of Jinan University, Guangdong 999 Brain Hospital, First Affiliated Hospital, Sun Yat-Sen University, Wuhan Women and Children's Medical Center, First People's Hospital, Shunde China
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1. Study Identification

Unique Protocol Identification Number
NCT03184597
Brief Title
HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions
Official Title
HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions: a Multicenter Clinical Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Unknown status
Study Start Date
August 1, 2017 (Actual)
Primary Completion Date
June 2021 (Anticipated)
Study Completion Date
June 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Second Affiliated Hospital of Guangzhou Medical University
Collaborators
Guangzhou First People's Hospital, West China Hospital, Guangdong Provincial People's Hospital, First Affiliated Hospital of Jinan University, Guangdong 999 Brain Hospital, First Affiliated Hospital, Sun Yat-Sen University, Wuhan Women and Children's Medical Center, First People's Hospital, Shunde China

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthema (MPE) and severe cutaneous reactions such as hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). cADRs are considered as a major public health issue because of their potentially life-threatening morbidity, especially severe cutaneous reactions. The incidence of SJS/TEN is estimated to vary from 1 in 1,000 to 10,000 drug exposures, and its mortality is as high as 35%. Antiepileptic drugs (AEDs), particularly those with aromatic ring structures such as carbamazepine (CBZ), oxcarbazepine (OXC), lamotrigine (LTG), phenobarbital (PB), and phenytoin (PHT), are among the most common causes of severe cutaneous reactions. The incidence of AED-induced SJS was estimated as 0.2% and all cases occurred in individuals receiving aromatic AEDs. Previous studies have validated that the human leukocyte antigen (HLA) allele HLA-B*15:02 is strongly associated with CBZ-induced SJS/TEN in southern Han Chinese and populations in southeast Asia. Our recent studies indicated that HLA-A*24:02 is a common genetic risk factor for CBZ-, LTG-, and PHT-induced SJS/TEN. It is also associated with MPE. Additionally, another four alleles, including HLA-B*15:01, HLA-B*15:11, HLA-A*02:01,and HLA-DRB1*01:01, were showed to be potential risk factors for aromatic AEDs-induced SJS/TEN. In 2007, the US Food and Drug Administration issued the safety alert that recommended HLA-B*15:02 screening for people with Asian ancestry before starting CBZ, and avoidance of the drug if the test is positive. Subsequent studies from Taiwan, Hong Kong and Thailand demonstrated that HLA-B*15:02 screening before commencing CBZ can significantly reduce the incidence of CBZ-induced SJS/TEN. However, the overall incidence of AEDs-induced SJS/TEN remained unchanged in Hong Kong, as PHT-induced SJS/TEN increased when CBZ-SJS/TEN decreased. Moreover, no study focuses on the incidences of AEDs-induced cADRs with and without HLA screening before commencing aromatic AEDs. Therefore, we are planning to conduct a multicenter prospective study to examine the reduction of AEDs-induced cADRs after the HLA screening prior to the beginning of aromatic AEDs administration.
Detailed Description
In this prospective study, 4000 or more patients from multicenters in southern China will be recruited. A HLA screening will be conducted before these patients start aromatic AEDs treatments. According to the HLA genotype, these patients will be divided into four groups that are three positive groups with different risk alleles and one negative group with no known risk allele. Aromatic AEDs were avoided or administrated with caution according to the risk level in the three positive groups, while they can be prescribed in the negative group. The effectiveness of HLA screening prior to the beginning of aromatic AEDs administration will be observed by the reduction of overall incidence of AEDs-induced cADRs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epilepsy, Neuropathy, Psychiatric Illness, Blepharospasm
Keywords
HLA screening, SJS/TEN, MPE, AEDs

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
4000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group with two strong risk factors
Arm Type
Experimental
Arm Description
When HLA screening before commencing aromatic AEDs shows positive for both HLA-A*24:02 and HLA-B*15:02 in a patient, aromatic AEDs were not administrated for this patient.
Arm Title
Group with one strong risk factors
Arm Type
Experimental
Arm Description
When HLA screening before commencing aromatic AEDs shows positive for HLA-B*15:02, carbamazepine (CBZ) was not administrated, and other aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead. When HLA screening before commencing aromatic AEDs shows positive for HLA-B*15:01 or HLA-A*24:02, aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead.
Arm Title
Group with one potential risk factors
Arm Type
Experimental
Arm Description
When HLA screening before commencing aromatic AEDs shows positive for any potential risk allele such as HLA-B*15:11, HLA-A*02:01and HLA-DRB1*01:01, aromatic AEDs were prescribed with caution or avoided if alternative non-aromatic AEDs can be prescribed instead.
Arm Title
Group without known risk factors
Arm Type
Experimental
Arm Description
When HLA screening before commencing aromatic AEDs shows negative for any known HLA risk allele , aromatic AEDs was administrated to these patients.
Intervention Type
Diagnostic Test
Intervention Name(s)
HLA screening before commencing aromatic AEDs
Intervention Description
When the risk HLA alleles are tested positive for the patients, aromatic AEDs were avoided or administrated with caution according to the risk level.
Primary Outcome Measure Information:
Title
AEDs-induced cADRs incidence
Description
the incidence of AEDs-induced cADRs within the first 3 months of commencing an aromatic AED
Time Frame
3 months

10. Eligibility

Sex
All
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Patients who are going to receive a kind of aromatic AEDs including CBZ, OXC, LTG, PHT, and PB as a new therapy. An AED was deemed newly commenced if there was no record of its prescription in at least the previous 12 months. Ethnic Han Chinese. None of the biological grandparents of the participants were from other races. Exclusion Criteria: individuals who are not of Han Chinese descent. individuals who had undergone bone marrow transplantation
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wei-Ping Liao, M.D.,Ph.D.
Phone
+86-20-34152625
Email
wpliao@163.net
First Name & Middle Initial & Last Name or Official Title & Degree
Na He, Ph.D.
Phone
+86-20-34152640
Email
henachilli@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wei-Ping Liao, M.D.,Ph.D.
Organizational Affiliation
Second Affiliated Hospital of Guangzhou Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Second Affiliated Hospital of Guangzhou Medical Universty
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510260
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wei-Ping Liao, M.D., Ph.D.
Phone
+86-20-34152625
Email
wpliao@163.net
First Name & Middle Initial & Last Name & Degree
Na He
Phone
+86-20-34152640
Email
henachilli@163.com
First Name & Middle Initial & Last Name & Degree
Wei-Ping Liao, M.D., Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The clinical data and HLA genotype of the participant will be shared in the collaborators
IPD Sharing Time Frame
2017 July - 2021 July
Citations:
PubMed Identifier
28476759
Citation
Shi YW, Min FL, Zhou D, Qin B, Wang J, Hu FY, Cheung YK, Zhou JH, Hu XS, Zhou JQ, Zhou LM, Zheng ZZ, Pan J, He N, Liu ZS, Hou YQ, Lim KS, Ou YM, Hui-Ping Khor A, Ng CC, Mao BJ, Liu XR, Li BM, Kuan YY, Yi YH, He XL, Deng XY, Su T, Kwan P, Liao WP. HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology. 2017 Jun 6;88(23):2183-2191. doi: 10.1212/WNL.0000000000004008. Epub 2017 May 5.
Results Reference
background
PubMed Identifier
22348435
Citation
Shi YW, Min FL, Qin B, Zou X, Liu XR, Gao MM, Wang Q, Zhou JQ, Liao WP. Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502? Basic Clin Pharmacol Toxicol. 2012 Jul;111(1):58-64. doi: 10.1111/j.1742-7843.2012.00868.x. Epub 2012 Mar 17.
Results Reference
background
PubMed Identifier
21306565
Citation
Shi YW, Min FL, Liu XR, Zan LX, Gao MM, Yu MJ, Liao WP. Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. Basic Clin Pharmacol Toxicol. 2011 Jul;109(1):42-6. doi: 10.1111/j.1742-7843.2011.00681.x. Epub 2011 Mar 16.
Results Reference
background
PubMed Identifier
21428768
Citation
Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC, Tai CT, Wu SL, Lu CH, Hsu YC, Yu HY, Ro LS, Lu CT, Chu CC, Tsai JJ, Su YH, Lan SH, Sung SF, Lin SY, Chuang HP, Huang LC, Chen YJ, Tsai PJ, Liao HT, Lin YH, Chen CH, Chung WH, Hung SI, Wu JY, Chang CF, Chen L, Chen YT, Shen CY; Taiwan SJS Consortium. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011 Mar 24;364(12):1126-33. doi: 10.1056/NEJMoa1009717.
Results Reference
background
PubMed Identifier
25355835
Citation
Chen Z, Liew D, Kwan P. Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology. 2014 Nov 25;83(22):2077-84. doi: 10.1212/WNL.0000000000001034. Epub 2014 Oct 29.
Results Reference
background
PubMed Identifier
23895569
Citation
Rattanavipapong W, Koopitakkajorn T, Praditsitthikorn N, Mahasirimongkol S, Teerawattananon Y. Economic evaluation of HLA-B*15:02 screening for carbamazepine-induced severe adverse drug reactions in Thailand. Epilepsia. 2013 Sep;54(9):1628-38. doi: 10.1111/epi.12325. Epub 2013 Jul 29.
Results Reference
background
PubMed Identifier
26888992
Citation
Chen Z, Liew D, Kwan P. Real-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment. Neurology. 2016 Mar 22;86(12):1086-94. doi: 10.1212/WNL.0000000000002484. Epub 2016 Feb 17.
Results Reference
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HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions

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