The formation of carbamazepine metabolites and carbamazepine-protein conjugates in epilepsy patients

ISRCTN ISRCTN62125126
DOI https://doi.org/10.1186/ISRCTN62125126
EudraCT/CTIS number 2013-002743-28
Secondary identifying numbers 15543
Submission date
18/02/2015
Registration date
19/02/2015
Last edited
21/09/2021
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Carbamazepine is an effective drug that is used in the treatment of epilepsy, neuralgia and psychiatric disorders. Although generally well tolerated, it can cause hypersensitivity reactions such as a skin rash in up to 10% of patients. These reactions can result in hospital admission, long-term complications such as blindness, and can cause death in up to 30% of patients. These reactions are caused by the immune system. Recent research has identified that patients with specific genes are at a higher risk of developing this hypersensitivity. Carbamazepine is converted by the liver to other chemical products called metabolites. It is believed that one or more of these metabolites activate the immune system. However, it is not known how this happens. This aim of this study is to assess the stable and toxic products formed in the blood and urine of patients receiving carbamazepine.

Who can participate?
Adults aged at least 18 who have either just been prescribed carbamazepine or have received the treatment at the same dose for at least 4 weeks

What does the study involve?
Participants provide blood and urine samples in order to identify the chemicals responsible for triggering the immune system in susceptible people. Genetic variations are also analysed to determine their effects on carbamazepine.

What are the possible benefits and risks of participating?
These results may help to explain the variation in carbamazepine hypersensitivity between patients. Lessons learned from this research will provide valuable information for other drugs that cause similar hypersensitivity reactions (e.g. penicillins). Improved understanding of the mechanism of carbamazepine hypersensitivity will enable safer drug design in future and the development of predictive tests that can diagnose and identify patients susceptible to adverse reactions.

Where is the study run from?
University of Liverpool (UK)

When is the study starting and how long is it expected to run for?
November 2013 to April 2015

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Vincent Yip

Contact information

Dr Vincent Yip
Scientific

University of Liverpool
Wolfson Centre for Personalised Medicine
Department of Pharmacology
Block A: Waterhouse Buildings
1–5 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Study information

Study designNon-randomised; Both; Treatment
Primary study designInterventional
Secondary study designNon randomised study
Study setting(s)Other
Study typeTreatment
Participant information sheet Not available in web format, please use contact details to request a patient information sheet
Scientific titleA pharmacokinetic investigation into the formation of carbamazepine metabolites and carbamazepine-protein conjugates in epilepsy patients
Study acronymPICME II
Study objectivesThis study aims to improve our mechanistic understanding of carbamazepine hypersensitivity by using high sensitivity mass spectrometry to characterise and quantify the stable and toxic products formed in the blood and urine of patients receiving carbamazepine therapy.
Ethics approval(s)13/NW/0503
Health condition(s) or problem(s) studiedTopic: Neurological; Subtopic: Neurological (all Subtopics); Disease: Epilepsy
InterventionPatients in the auto-induction group will be newly prescribed carbamazepine. All other subjects in the study will have been prescribed carbamazepine by their neurologist as part of clinical care for patient for at least 4 weeks.
Intervention typeDrug
Pharmaceutical study type(s)
PhaseNot Applicable
Drug / device / biological / vaccine name(s)Carbamazepine
Primary outcome measurePharmacokinetic analyses; Timepoint(s): Time points dependent on time of presentation to clinic
Secondary outcome measuresN/A
Overall study start date05/11/2013
Completion date30/04/2015

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participantsPlanned Sample Size: 158; UK Sample Size: 158
Key inclusion criteriaAutoinduction group:
1. Subject is willing and able to give written informed consent
2. Subject is aged 18 or over
3.Subject is newly prescribed carbamazepine by their attending physician

Maintenance group:
1. Subject is willing and able to give written informed consent
2. Subject is aged 18 or over
3. Subject has received CBZ therapy at the same dosage for at least 4 weeks
Key exclusion criteriaAutoinduction group:
1. Subject is not willing to take part or unable to give written informed consent
2. Subject has in the past 4 weeks received other medication that is a CYP3A4 inducer or inhibitor (see medications below)
3. Subject has taken part on another research study within 90 days of commencement
4. Subject has any condition which in the opinion of the investigator will interfere with the study

Excluded medications:
Rifampicin, Amiodarone, Fluvoxamine, Saquinavir, Rifampin, Amprenavir, Indinavir, SVerapamil, Isoniazid, Atazanavir, Lopinavir, Verapamil, Phenytoin, Azithromycin, Mifepristone, Phenobarbital, Grapefruit juice, Nelfinavir, Omeprazole, Clarithromycin, Norverapamil, Clotrimazole, Cyclosporine A, Ritonavir, HMGCoA reductase inhibitors, Delavirdine, Ndesmethylerythromycin, Cyclophosphamide, Erythromycin, Roxithromycin, Spironolactone, Fluoxetine, RVerapamil

Maintenance group:
1. Subject is not willing to take part or unable to give written informed consent
2. Subject has any condition which in the opinion of the investigator will interfere with the study
Date of first enrolment05/11/2013
Date of final enrolment30/04/2015

Locations

Countries of recruitment

  • England
  • United Kingdom

Study participating centre

University of Liverpool
Wolfson Centre for Personalised Medicine
Department of Pharmacology
Block A: Waterhouse Buildings
1–5 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Sponsor information

University of Liverpool
University/education

Head of Division of Primary Care
Whelan Building
Quadrangle
Brownlow Hill
Liverpool
L69 3GB
England
United Kingdom

ROR logo "ROR" https://ror.org/04xs57h96

Funders

Funder type

Government

Medical Research Council
Government organisation / National government
Alternative name(s)
Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location
United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration

2016 thesis in https://core.ac.uk/download/pdf/80777101.pdf (added 24/07/2020)
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article 01/06/2021 21/09/2021 Yes No
HRA research summary 28/06/2023 No No

Editorial Notes

21/09/2021: Publication reference added.
24/07/2020: Thesis added.
07/07/2017: Plain English summary added.