Condition category
Nervous System Diseases
Date applied
02/06/2011
Date assigned
07/06/2011
Last edited
02/03/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Many mothers require long-term treatment with drugs to manage epilepsy, called antiepileptic drugs (AEDs). The levels of these drugs in the blood usually fall in pregnancy. This may increase the risk of seizures. Currently, some doctors carry out regular blood tests to check the level of the drugs in the blood in pregnancy. They offer to increase the dose if the levels fall compared to the last level. This is called therapeutic drug monitoring (TDM). Other doctors do not carry out regular blood tests in pregnancy. They only increase the dose if seizures worsen or if they occur for the first time in pregnancy. This is called clinical features monitoring (CFM). This study aims to find the AED monitoring method that is best and safest for seizure control in pregnancy. Currently, there is not enough evidence to strongly recommend one method of monitoring over the other in pregnancy.

Who can participate?
Pregnant women who are known to have epilepsy and are currently on one or more of the following drugs: carbamazepine, lamotrigine, levetiracetam or phenytoin.

What does the study involve?
Participants are seen as usual in a hospital antenatal clinic, every 4 weeks up until 6 weeks after they given birth. They are asked to:
1. Have regular blood tests every 4 weeks to check the drug (AED) levels in their blood until labour or delivery. The blood samples are stored for the lifetime of the trial and for 3 years after the completion of the trial. After this period, the samples are destroyed.
2. Complete a seizure diary throughout their pregnancy and up to 6 weeks after birth to document the type and frequency of any seizures they may experience, including any side effects.
3. Complete questionnaires about general well being (quality of life) at each clinic visit.
4. Provide a sample of blood from the umbilical cord after it has been cut. This will give us information on the level of AED in the baby’s blood at birth. When the baby is 6 weeks old, at a routine 6-week postnatal appointment, we will assess clinical information about the participant and her baby. Participants and their babies may be requested to attend a long-term follow-up appointment about five years after delivery. Participants can choose whether or not to participate in this visit.
5. Complete a questionnaire about any out of pocket expenses (e.g. transport costs, time lost from work or child care costs) they may have incurred when attending the clinics. This will help us find out about the wider cost implications of the two monitoring methods on the health service.

What are the possible benefits and risks of participating?
As we do not know the best method to monitor drugs in pregnancy, we cannot say if there will be any direct benefit to the participant and/or her baby. However, taking part in this study will help inform decisions about management of pregnant women with epilepsy in the future.
Participants may have side effects related to the type and dose of AED. It is expected that they will continue to take their usual AEDs, as it is less likely for these to be changed during pregnancy. If it is necessary to increase/decrease the dose of AEDs or change them, then the reasons for this will be discussed with the participant and their clinician/nurse in the usual way, giving them the opportunity to discuss concerns about the process.

Where is the study run from?
The study takes place at various joint neurology obstetric antenatal clinics or high-risk clinics at hospitals throughout the United Kingdom, with a total of 41 centres expressing interest or participating.

When is the study starting and how long is it expected to run for?
Patients will be enrolled in the study between November 2011 and October 2013. Follow-up examinations will continue until April 2014.

Who is funding the study?
NIHR Health Technology Assessment Programme (UK).

Who is the main contact?
Prof Khalid Khan
k.s.khan@qmul.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Khalid Khan

ORCID ID

Contact details

Women’s Health Research Unit
Centre for Primary Care and Public Health
Blizard Institute
Barts and The London School of Medicine and Dentistry
Yvonne Carter Building
58 Turner Street
London
E1 2AB
United Kingdom
-
k.s.khan@qmul.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

HTA 09/55/38

Study information

Scientific title

AntiEpileptic drug Monitoring In PREgnancy: an evaluation of effectiveness, cost-effectiveness and acceptability of monitoring strategies

Acronym

EMPIRE

Study hypothesis

Does therapeutic drug monitoring (TDM), among pregnant women with epilepsy on antiepileptic drugs (AEDs), reduce the risk of seizure deterioration compared to clinical features monitoring (CFM) alone?
1. What is the effect of TDM Vs CFM on quality life in pregnant women on anti epileptic drugs?
2. Is there a difference in the total AED exposure between TDM and CFM monitoring strategies?
3. What, if any, is the relationship between level of fall in serum AED levels and seizures?
4. What are the adverse effects of AED exposure on mother and foetus?
5. What are the views and experiences of pregnant women with epilepsy?
6. What is the most cost-effective method of monitoring for the health service?

Ethics approval

Coventry & Warwickshire REC approval pending as of 03/06/2011

Study design

A multicentre randomised controlled trial within a cohort study and a qualitative study of patient acceptability

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use contact details below to request a patient information sheet

Condition

Epilepsy in pregnancy

Intervention

Relevant neurological and obstetric history will be obtained from pregnant women with epilepsy at booking / antenatal visit. Baseline data will be collected on age, ethnicity, age at first seizure (excluding febrile seizures), seizure frequency over the previous 6 months, seizure types, epilepsy syndrome, aetiology of epilepsy, duration of epilepsy, current AED and dose, baseline AED level, learning difficulty, any neurological signs, school leaving age, educational performance, current employment, previous AED pregnancy exposure, previous pregnancy complications, perinatal outcome, number of children, health of child and educational status of child at the first visit.

There are 3 groups - The treatment groups will be clinical features monitoring alone versus therapeutic drug monitoring (for some centres around the UK clinical features monitoring is usual practice whereas in other therapeutic drug monitoring is usual practice). The third group will be participants whose blood AED levels remain stable.

Women will be followed up in the usual way every 4 weeks. Serum AED levels will be obtained but results will be kept blinded. Details of seizures, responses to QoL questionnaire and obstetric assessments will be recorded 4 weekly. A seizure diary specially developed for collecting trial data will be obtained but results will be kept blinded. It will provide details of type of seizure, frequency of seizure in the last 4 weeks and any side effects from the medication. The daily dose of AED and any increase will be recorded.

The foetus will be evaluated by detailed ultrasound scan at 20 weeks for congenital abnormalities and serial growth scans if fetal growth restriction is suspected. Foetal outcomes will be collected antenatal, at delivery and 6 weeks after delivery. An online data entry system, with appropriate security, will allow physicians, and specialist nurses to enter data directly.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

Time from randomisation to first seizure and time to first tonic clonic seizure throughout pregnancy up to and including six weeks post-delivery. Statistical analysis will take into account the time to each ‘event’ per woman over the whole period of monitoring. Participants will be asked to document the occurrence of each seizure by frequency and type in a trial specific seizure diary.

Secondary outcome measures

Maternal:
1.Neurological
1.1. Percentage of women experiencing seizures who were seizure free in three month prior to consent. Number of seizures per week and number of seizure free days per week throughout pregnancy and up to and including six weeks post delivery
1.2. Serum levels of AED in each trimester, daily dose exposure by trimester, cumulative dose exposure for pregnancy, adverse events as measured by the Liverpool Adverse Events Profile
2. Obstetric
Maternal death, mode of delivery, preterm labour, induction of labour, pre eclampsia, antepartum and postpartum haemorrhage, admission to high dependency/ intensive care unit, breast feeding, infection, gestational diabetes mellitus
3. Quality of Life: Epilepsy specific QoL as measured by QOLIE-31, generic QoL as measured by EQ-5D

Foetal and neonatal:
Major and minor congenital malformation: major congenital malformations defined as structural abnormalities with surgical, medical or cosmetic importance at antenatal or post natal diagnosis. Apgar score at 1’ and 5’ minutes, admission to neonatal unit, birth weight, head circumference, foetal growth, stillbirths, neonatal deaths, Bayley Scales of Infant Development (BSID).

Overall trial start date

01/07/2011

Overall trial end date

31/03/2016

Reason abandoned

Eligibility

Participant inclusion criteria

1. Have signed a consent form before undergoing any trial-related activities
2. Have a confirmed viable pregnancy of less than 16 weeks gestation at booking
3. Have a confirmed diagnosis of epilepsy (any syndrome: primary, localised or unclassified)
4. Currently prescribed lamotrigine monotherapy or polytherapy (with carbamazepine, phenytoin or levetiracetam), carbamazepine monotherapy, phenytoin monotherapy or levetiracetam monotherapy
5. Be capable of understanding the information provided, with use of an interpreter if required

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

1000

Participant exclusion criteria

1. Be beyond 16 weeks gestation at booking
2. Documented non-epileptic seizures in the last 2 years
3. Documented of status epilepticus in the last 12 months
4. A history of alcohol or substance abuse or dependence in the last 2 years
5. Sodium valproate (VPA) monotherapy or polytherapy
6. Non lamotrigine polytherapy
7. A history of poor AED adherence
8. Unable to complete a seizure diary or recall frequency of seizures accurately
9. Have a significant learning disability
10. Participation in any blinded, placebo-controlled trials of investigational medicinal products in pregnancy

Recruitment start date

01/07/2011

Recruitment end date

31/08/2014

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Barts and The London School of Medicine and Dentistry
Women’s Health Research Unit Centre for Primary Care and Public Health Blizard Institute Barts and The London School of Medicine and Dentistry Yvonne Carter Building 58 Turner Street
London
E1 2AB
United Kingdom

Trial participating centre

Royal Jubilee Maternity Hospital
274 Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Trial participating centre

Queen Elizabeth Maternity Unit
1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
51 Little France Cres
Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

Royal Gwent Hospital  
Cardiff Road
Newport
NP20 2UB
United Kingdom

Trial participating centre

Nevill Hall Hospital  
Brecon Road Abergavenny
Monmouthshire
NP7 7EG
United Kingdom

Trial participating centre

Glan Clwyd Hospital  
Rhuddlan Road
Rhyl
LL18 5UJ
United Kingdom

Trial participating centre

Morriston Hospital  
Heol Maes Eglwys Morriston
Swansea
SA6 6NL
United Kingdom

Trial participating centre

University Hospital of Wales, Cardiff & Vale
Longcross Street Cardiff
South Glamorgan
CF24 0SZ
United Kingdom

Trial participating centre

Royal Victoria Infirmary  
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom

Trial participating centre

Sunderland Royal Hospital  
Kayll Road
Sunderland
SR4 7TP
United Kingdom

Trial participating centre

University Hospital of North Durham
North Road
Durham
DH1 5TW
United Kingdom

Trial participating centre

Jessops Wing
Tree Root Walk, S10 2
Sheffield
S10 2
United Kingdom

Trial participating centre

Leeds General Infirmary  
Great George Street
Leeds
LS1 3EX
United Kingdom

Trial participating centre

Warrington Hospital
Lovely Ln Warrington
Cheshire
WA5 1QG
United Kingdom

Trial participating centre

Liverpool Women's Hospital
Liverpool
L8 7SS
United Kingdom

Trial participating centre

Royal Blackburn Hospital  
Haslingden Rd
Blackburn
BB2 3HH
United Kingdom

Trial participating centre

Burnley General Hospital  
Burnley General Hospital   Casterton Avenue
Burnley, Lancashire
BB10 2PQ
United Kingdom

Trial participating centre

St Marys Hospital, Central Manchester University Hospitals
Manchester
M13 9WL
United Kingdom

Trial participating centre

The Royal Derby Hospital
Uttoxeter Rd
Derby
DE22 3NE
United Kingdom

Trial participating centre

Stafford Hospital
Weston Rd
Stafford
ST16 3SA
United Kingdom

Trial participating centre

University Hospital of North Staffordshire, Maternity UHNS

Stoke-on-Trent
ST4 6QG
United Kingdom

Trial participating centre

Royal Shrewsbury Hospital
Mytton Oak Rd Shrewsbury
Shropshire
SY3 8XQ
United Kingdom

Trial participating centre

Birmingham Women's Hospital
Mindelsohn Way
Birmingham
B15 2TG
United Kingdom

Trial participating centre

Birmingham City Hospital
Dudley Rd
Birmingham
B18 7QH
United Kingdom

Trial participating centre

Northampton General Hospital
Cliftonville
Northampton
NN1 5BD
United Kingdom

Trial participating centre

University Hospitals of Leicester, Women's Hospital
Leicester
-
United Kingdom

Trial participating centre

University Hospitals of Coventry & Warwickshire
Clifford Bridge Rd Coventry
West Midlands
CV2 2DX
United Kingdom

Trial participating centre

Worcestershire Royal Hospital
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Trial participating centre

John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Queen's Hospital, Barking, Haveridge & Redbridge University Hospitals
Rom Valley Way Romford
Essex
RM7 0AG
United Kingdom

Trial participating centre

Whipps Cross Hospital
Whipps Cross Road
London
E11 1NR
United Kingdom

Trial participating centre

Newham University Hospital
Glen Rd
London
E13 8SL
United Kingdom

Trial participating centre

The Royal London
Whitechapel Rd
London
E1 1BB
United Kingdom

Trial participating centre

St Thomas' Hospital
Westminster Bridge Rd
London
SE1 7EH
United Kingdom

Trial participating centre

Chelsea & Westminster Hospital
369 Fulham Rd
London
SW10 9NH
United Kingdom

Trial participating centre

St Georges Hospital
Blackshaw Rd
London
SW17 0QT
United Kingdom

Trial participating centre

St Richard's Hospital
Spitalfield Lane
Chichester
PO19 6SE
United Kingdom

Trial participating centre

Worthing Hospital
Lyndhurst Rd Worthing
West Sussex
BN11 2DH
United Kingdom

Trial participating centre

Frimley Park Hospital
Portsmouth Road Frimley
Surrey
GU16 7UJ
United Kingdom

Trial participating centre

Royal Sussex County Hospital
Eastern Rd
Brighton
BN2 5BE
United Kingdom

Trial participating centre

Southend Hospital
Prittlewell Chase
Westcliff-on-Sea
SS0 0RY
United Kingdom

Trial participating centre

Colchester General Hospital
Turner Rd
Colchester
CO4 5JL
United Kingdom

Trial participating centre

Royal Hampshire County Hospital
Romsey Rd
Winchester
SO22 5DG

Trial participating centre

Basingstoke and North Hampshire Hospital
Aldermaston Rd Basingstoke
Hampshire
RG24 9NA

Trial participating centre

Queen Alexandra Hospital
Southwick Hill Rd
Portsmouth
PO6 3LY
United Kingdom

Trial participating centre

Princess Anne Hospital
Coxford Rd Southampton
Hampshire
SO16 5YA
United Kingdom

Trial participating centre

Gloucester Royal Hospital
Great Western Rd
Gloucester
GL1 3NN
United Kingdom

Trial participating centre

Royal Cornwall Hospital
2 Penventinnie Ln Treliske
Truro, Cornwall
TR1 3LQ
United Kingdom

Trial participating centre

North Middlesex Hospital
Sterling Way
London
N18 1QX
United Kingdom

Trial participating centre

Bradford Royal Infirmary
Duckworth Ln Bradford
Yorkshire
BD9 6RJ
United Kingdom

Sponsor information

Organisation

Queen Mary, University of London

Sponsor details

Queen Mary Innovation Centre
5 Walden Street
Whitechapel
London
E1 2EF
United Kingdom
-
sponsorsrep@bartshealth.nhs.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

02/03/2016: Added Bradford Royal Infirmary as a trial participating centre 01/03/2016: Added 50 trial participating centres to record 10/02/2016: Changed recruitment end date and overall end date from 01/02/2015 to 31/08/2014 and 31/03/2016 respectively. The sponsor email address was changed from gerry.leonard@bartsandthelondon.nhs.uk to sponsorsrep@bartshealth.nhs.uk. The details for both the trial participating centre and contact details were changed from "Centre for Health Sciences, Barts and The London School of Medicine and Dentistry, 2 Newark Street" to "Women’s Health Research Unit Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Yvonne Carter Building, 58 Turner Street".