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

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ClinicalTrials.gov Identifier: NCT03184597
Recruitment Status : Recruiting
First Posted : June 12, 2017
Last Update Posted : September 5, 2018
Sponsor:
Collaborators:
Guangzhou First People's Hospital
West China Hospital
Guangdong General 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
Information provided by (Responsible Party):
Second Affiliated Hospital of Guangzhou Medical University

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.


Condition or disease Intervention/treatment Phase
Epilepsy Neuropathy Psychiatric Illness Blepharospasm Diagnostic Test: HLA screening before commencing aromatic AEDs Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4000 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions: a Multicenter Clinical Study
Actual Study Start Date : August 1, 2017
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
Experimental: Group with two strong risk factors
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.
Diagnostic Test: HLA screening before commencing aromatic AEDs
When the risk HLA alleles are tested positive for the patients, aromatic AEDs were avoided or administrated with caution according to the risk level.

Experimental: Group with one strong risk factors

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.

Diagnostic Test: HLA screening before commencing aromatic AEDs
When the risk HLA alleles are tested positive for the patients, aromatic AEDs were avoided or administrated with caution according to the risk level.

Experimental: Group with one potential risk factors
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.
Diagnostic Test: HLA screening before commencing aromatic AEDs
When the risk HLA alleles are tested positive for the patients, aromatic AEDs were avoided or administrated with caution according to the risk level.

Experimental: Group without known risk factors
When HLA screening before commencing aromatic AEDs shows negative for any known HLA risk allele , aromatic AEDs was administrated to these patients.
Diagnostic Test: HLA screening before commencing aromatic AEDs
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 Measures :
  1. AEDs-induced cADRs incidence [ Time Frame: 3 months ]
    the incidence of AEDs-induced cADRs within the first 3 months of commencing an aromatic AED



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03184597


Contacts
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Contact: Wei-Ping Liao, M.D.,Ph.D. +86-20-34152625 wpliao@163.net
Contact: Na He, Ph.D. +86-20-34152640 henachilli@163.com

Locations
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China, Guangdong
The Second Affiliated Hospital of Guangzhou Medical Universty Recruiting
Guangzhou, Guangdong, China, 510260
Contact: Wei-Ping Liao, M.D., Ph.D.    +86-20-34152625    wpliao@163.net   
Contact: Na He    +86-20-34152640    henachilli@163.com   
Principal Investigator: Wei-Ping Liao, M.D., Ph.D.         
Sponsors and Collaborators
Second Affiliated Hospital of Guangzhou Medical University
Guangzhou First People's Hospital
West China Hospital
Guangdong General 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
Investigators
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Principal Investigator: Wei-Ping Liao, M.D.,Ph.D. Second Affiliated Hospital of Guangzhou Medical University

Publications:

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Responsible Party: Second Affiliated Hospital of Guangzhou Medical University
ClinicalTrials.gov Identifier: NCT03184597     History of Changes
Other Study ID Numbers: 2017-hs-30
First Posted: June 12, 2017    Key Record Dates
Last Update Posted: September 5, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The clinical data and HLA genotype of the participant will be shared in the collaborators
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: 2017 July - 2021 July

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Second Affiliated Hospital of Guangzhou Medical University:
HLA screening
SJS/TEN
MPE
AEDs

Additional relevant MeSH terms:
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Blepharospasm
Mental Disorders
Eyelid Diseases
Eye Diseases
Anticonvulsants