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S T U D Y P R O T O C O L Open Access
Lamotrigine versus inert placebo in the
treatment of borderline personality
disorder: study protocol for a randomized
controlled trial and economic evaluation
Mike J. Crawford
1*
, Rahil Sanatinia
1
, Barbara Barrett
2
, Sarah Byford
2
, Gillian Cunningham
3
, Kavi Gakhal
1
,
Geof Lawrence-Smith
4
, Verity Leeson
1
, Fenella Lemonsky
1
, Georgia Lykomitrou
5
, Alan Montgomery
5
,
Richard Morriss
5
, Carol Paton
4
, Wei Tan
5
, Peter Tyrer
1
and Joseph G. Reilly
3
Abstract
Background: People with borderline personality disorder (BPD) experience rapid and distressing changes in mood,
poor social functioning and have high rates of suicidal behaviour. Several small scale studies suggest that mood
stabilizers may produce short-term reductions in symptoms of BPD, but have not been large enough to fully
examine clinical and cost-effectiveness.
Methods/Design: A two parallel-arm, placebo controlled randomized trial of usual care plus either lamotrigine or
an inert placebo for people aged over 18 who are using mental health services and meet diagnostic criteria for
BPD. We will exclude people with comorbid bipolar affective disorder or psychosis, those already taking a mood
stabilizer, those who speak insufficient English to complete the baseline assessment and women who are pregnant
or contemplating becoming pregnant. Those meeting inclusion criteria and provide written informed consent will
be randomized to up to 200mg of lamotrigine per day or an inert placebo (up to 400mg if taking combined oral
contraceptives).
Participants will be randomized via a remote web-based system using permuted stacked blocks stratified by study
centre, severity of personality disorder, and level of bipolarity.
Follow-up assessments will be conducted by masked researchers 12, 24 weeks, and 52 weeks after randomization.
The primary outcome is the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). The secondary
outcomes are depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource
use and costs, side effects of treatment, adverse events and withdrawal of trial medication due to adverse effects.
The main analyses will use intention to treat without imputation of missing data. The economic evaluation will take
an NHS/Personal Social Services perspective. A cost-utility analysis will compare differences in total costs and
differences in quality of life using QALYs derived from the EQ-5D.
Discussion: The evidence base for the use of pharmacological treatments for people with borderline personality
disorder is poor. In this trial we will examine the clinical and cost-effectiveness of lamotrigine to assess what if any
impact offering this has on peoples’mental health, social functioning, and use of other medication and other
resources.
Trial registration: Current Controlled Trials ISRCTN90916365 (registered 01/08/2012)
Keywords: Borderline personality disorder, Mood stabilizer, Lamotrigine, Randomized trial
* Correspondence: m.crawford@imperial.ac.uk
1
Centre for Mental Health, Imperial College London, Du Cane Road, London
W12 ONN, UK
Full list of author information is available at the end of the article
TRIALS
© 2015 Crawford et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Crawford et al. Trials (2015) 16:308
DOI 10.1186/s13063-015-0823-x
Background
People with borderline personality disorder (BPD)
have disturbances in mood which include affective in-
stability, outbursts of anger, and feelings of emptiness.
These are accompanied by negative thoughts about
self and poor interpersonal functioning [1]. As many
as 2 % of people have BPD [2], and levels are far
higher among those in contact with mental health
services, particularly inpatient units, where up to a
fifth of people may have this diagnosis [3]. People
with BPD have poor social functioning, are socially
isolated, and are usually unemployed or on long-term
sick leave [4]. They also have high rates of deliberate
self-harm and a rate of completed suicide that is 50
times that in the general population [5].
No drugs are currently licensed for BPD; however,
people with this condition are usually prescribed large
amounts of psychotropic medication [6]. The prominence
of affective instability among people with BPD has led to
interest in the role that mood stabilizers might play in
helping people with this condition. Concerns about
toxicity in overdose and harm to children born to women
taking these drugs have limited research to date. Evidence
from cohorts of people receiving treatment for epilepsy
suggests that valproate and lamotrigine may be safer in
overdose than carbamazepine [7] and that congenital mal-
formations are more common among people taking
valproate than among those taking lamotrigine [8].
To date, there have been two small-scale random-
ized trials of lamotrigine. The first involved 24
women recruited mainly from advertisements placed
in primary care practices. In comparison with people
taking placebo, those taking up to 200 mg of lamotrigine
daily were found to have lower levels of anger 8 weeks
later [9]. The second trial recruited 28 men and women
through websites and television and radio advertisements.
Those randomly assigned to receive up to 225 mg of
lamotrigine were found to have lower levels of affective in-
stability and impulsiveness 12 weeks later [10]. These
studies have a number of limitations, including their focus
on short-term outcomes, small sample sizes, and the ab-
sence of an economic evaluation. Furthermore, people
who took part in them may not have had the degree of se-
verity of the disorder that is seen among people who are
generally receiving treatment in secondary care mental
health services. Although these studies have demonstrated
the feasibility of randomized trials for people with BPD,
they have not been sufficiently large to fully test the clin-
ical effectiveness and cost-effectiveness of this approach to
trying to help people with this condition.
Research objectives
The main objectives of the study are to find out whether
adding lamotrigine to usual care for people with BPD,
compared with those prescribed an inert placebo, im-
proves mental health, social functioning, and quality of
life and whether it reduces the incidence of suicidal be-
haviour and lowers the amount of anti-psychotic and
other psychotropic medication that people are pre-
scribed. We will also examine whether adding lamotri-
gine to usual care for people with BPD, compared with
those prescribed an inert placebo, is associated with a
higher incidence of side effects and whether adding
lamotrigine provides a cost-effective use of resources.
Methods/Design
The LABILE trial (Lamotrigine And Borderline per-
sonality disorder: Investigating Long-term Effective-
ness trial) is a multi-centre, two-arm, parallel group,
double-blind, placebo-controlled randomized trial with
3-, 6-, and 12-month follow-up assessment. The trial
includes an integrated clinical and economic evalu-
ation. A summary of trial design is presented in
Fig. 1.
Study setting
Study participants will be recruited from secondary care
mental health services in England, including inpatient
units, outpatient clinics, and community mental health
teams. There are six recruitment centres in London
(Central and North West London NHS Foundation Trust,
Oxleas NHS Foundation Trust, and West London Mental
Health NHS Trust), the East Midlands (Nottinghamshire
Healthcare NHS Foundation Trust and Derbyshire
Healthcare NHS Foundation Trust), and the North East of
England (Tees, Esk and Wear Valleys Foundation NHS
Trust).
Eligibility criteria
The target population is adults who are at least 18
years old and who meet DSM-IV (Diagnostic and Stat-
istical Manual of Mental Disorders, 4th Edition) diag-
nostic criteria for BPD [1] and are willing and able to
provide written informed consent to take part in the
study. Eligibility will be assessed by trained re-
searchers. Exclusion criteria are the following:
i). current or past comorbid bipolar affective disorder
(type I and II) or psychotic disorder (schizophrenia,
schizoaffective disorder, or mood disorder with
psychotic features),
ii). currently receiving a mood stabilizer (lithium,
carbamazepine, or valproate) or have done so within
the previous four weeks,
iii). known medical history of liver or kidney impairment,
iv). cognitive or language difficulties that would
preclude people from providing informed consent,
and
Crawford et al. Trials (2015) 16:308 Page 2 of 10
v). any woman who is pregnant or planning a
pregnancy or any woman of child-bearing age unless
using adequate contraception.
Interventions
Those in the active arm of the trial will receive encapsu-
lated generic lamotrigine titrated according to the estab-
lished British National Formulary protocol (http://
www.bnf.org/bnf/index.htm) but with the titration oc-
curring at standardised 14-day intervals. The dose will
be altered if participants are also taking the combined
oral contraceptive pill, which affects the metabolism of
lamotrigine. For those not taking the combined oral
contraceptive pill, the starting dose will be 25 mg per
day. Depending on the response and tolerance, it will be
increased to 50 mg after 2 weeks, 100 mg after 4 weeks,
and 200 mg per day after 6 weeks and thereafter. For
those who are taking the combined oral contraceptive
pill, the starting dose will be 25 mg per day. This will be
increased to 50 mg after 2 weeks, 100 mg after 4 weeks,
200 mg after 6 weeks, 300 mg after 8 weeks, and 400 mg
per day after 10 weeks.
Fig. 1 Study flow chart
Crawford et al. Trials (2015) 16:308 Page 3 of 10
Trial medication will be issued to patients fortnightly to
cover the dose titration period, and subsequent 4-weekly
packs will be issued once the maintenance dose is reached.
This will ensure that non-adherence and subsequent study
withdrawal are dealt with promptly and that large supplies
of medication cannot be accumulated by patients who
may be at risk of overdosing. Supplies will be issued by
the relevant hospital pharmacy services. The lamotrigine
and placebo capsules will be kept in a suitable
temperature-controlled environment at each site.
Those in the placebo arm of the trial will receive
capsules, identical in appearance to those containing
active lamotrigine, but backfilled instead with lactose
monohydrate. This will be prescribed in the same re-
gimeasthatusedintheactivearmofthetrial.
Usual care will comprise contact with primary and
secondary health services, including access to psycho-
logical treatment services and inpatient admission if re-
quired. No restrictions will be imposed on the use of
other treatments, except that those who remain in the
trial will not be prescribed lamotrigine (aside from trial
medication) or another anti-epileptic mood stabilizer
(lithium, carbamazepine, or sodium valproate). There-
fore, our approach will be primarily to record the use of
all other medication, document details of dosage, and
ensure the follow-up of all randomly assigned partici-
pants, irrespectively of the medication they subsequently
receive.
In accordance with the current revision of the Declar-
ation of Helsinki (amended October 2000, with add-
itional footnotes added 2002 and 2004), a participant
will have the right to stop trial treatment and to with-
draw from the trial at any time and for any reason, with-
out prejudice to his or her future medical care by the
physician or at the institution, and is not obliged to give
his or her reasons for doing so. The investigator may
withdraw a participant from trial treatment at any time
in the interests of the participant’s health and well-being
or for administrative reasons. A trial participant will be
withdrawn from taking the trial medication if he or she
experiences a rash that is clinically judged as being asso-
ciated with lamotrigine. The date and reason for termin-
ation of treatment will be recorded. Trial follow-ups will
continue after treatment has been withdrawn, unless the
participant withdraws consent.
Assessments
The timing and sequence of all assessments are sum-
marised in Table 1.
Baseline
At baseline, we will assess eligibility by using the
Structured Clinical Interview for Axis II Personality
Disorders (SCID-II) [11]. The SCID-II provides a
reliable assessment of BPD [12], has a shorter admin-
istration time than other semi-structured interviews
used to assess BPD, and can be completed within 1
h. We will use data from the SCID-II to establish the
severity of the participant’s personality disorder [13].
We will use the Structured Clinical Interview for Axis
I Disorders (SCID-I) [14] to assess whether potential
participants have bipolar affective disorder (type I and
II) and to exclude those who do. Hypomanic symp-
toms will be assessed by using the Hypomanic Check-
list [15], a relatively short screening questionnaire
that can distinguish those with bipolar disorder from
those with unipolar depression.
Primary outcome
The primary outcome is symptoms of BPD measured
by using the Zanarini Rating Scale for Borderline Per-
sonality Disorder (ZAN-BPD) [16] 52 weeks after ran-
domization. The ZAN-BPD is a widely used measure
of symptoms and behavioural problems experienced
by people with BPD. It includes measures of anger, impul-
sivity, and affective instability. The ZAN-BPD has been
used in previous studies of pharmacological and psycho-
logical treatments for people with BPD [10, 17, 18]. It is
reliable (intraclass correlation coefficients for inter-rater
reliability of 0.96 and test-retest reliability of 0.93), has
high convergent validity with structured clinical ratings
of symptoms of BPD (e.g., Revised Diagnostic Interview
for Borderlines), and is sensitive to change [16].
Secondary outcomes
1) Scores on the ZAN-BPD in the 52 weeks after
randomization using repeated measures analysis of
data collected at 12-, 26-, and 52-week follow-up.
2) Total score on the 21-item Beck Depression
Inventory [19] at 12, 24, and 52 weeks. The Beck
Depression Inventory has been widely used as a
self-completed questionnaire, provides a valid assess-
ment of the severity of depressive symptoms, and
can be completed in less than 10 min [20].
3) Incidence and severity of suicidal behaviour, assessed
by using the Acts of Deliberate Self-Harm Inventory
[21] at 12, 24, and 52 weeks. This structured inter-
view collects detailed information about the number
and severity of episodes of self-harm and has been
used successfully in other trials of treatments for
people with BPD [22].
4) Social functioning, assessed by using the Social
Functioning Questionnaire at 12, 24, and 52 weeks.
This questionnaire is an eight-item self-report scale
that asks people about problems across a range of
settings that people with personality disorder often
experience [23].
Crawford et al. Trials (2015) 16:308 Page 4 of 10
5) Health-related quality of life, assessed by using the
EuroQoL-5D (European quality of Life-5 dimensions)
[24] at 12, 24, and 52 weeks. The EuroQOL-5D pro-
vides a brief and reliable measure of health-related
quality of life and is responsive to change in people
with BPD [25].
6) Side effects, assessed at 12, 24, and 52 weeks by
using a pro forma designed to cover the possible
side effects listed in the British National Formulary
entry for lamotrigine [26].
7) Use of alcohol and other drugs at 52 weeks, assessed
by using the Alcohol, Smoking and Substance
Involvement Screening Test (ASSIST) [27]. This
short questionnaire provides a reliable and valid
screening test for problem substance use [28].
8) Use of concomitant anti-psychotic and other
psychotropic medication defined as the proportion
of people taking anti-psychotics, anti-depressants,
benzodiazepines, and hypnotics 24 and 52 weeks
after randomization.
9) Total cost of health and social services; resource use
information will be collected at 12, 24, and 52 weeks
by using the Adult Service Use Schedule adapted for
use in this trial on the basis of previous research
involving people with personality disorders [29].
This questionnaire collects detailed data on the use
of all hospital and community health and social care
services.
All assessments will be conducted by researchers who
have been trained to use study instruments by clinicians
with expertise in the assessment of people with person-
ality disorder.
Adherence
Adherence with study medication will be assessed at 12-,
24-, and 52-week assessments by using the Morisky Scale
[30]. This is a four-item questionnaire which provides a
valid estimate of adherence with psychotropic medication.
In addition, researchers will ask participants about their
use of medication when each prescription is renewed and
record any treatment breaks.
Sample size
The sample size calculation for the study is based on our
primary hypotheses that, for people with BPD who are in
contact with mental health services, the addition of lamo-
trigine to their usual treatment will reduce symptoms of
their disorder at 52-week follow-up, according to the
ZAN-BPD. The ZAN-BPD has been used to examine the
clinical effectiveness of a range of psychological and
pharmacological treatments for people with BPD. In a trial
of problem-solving therapy compared with treatment as
usual, Blum and colleagues [17] found improvements in
mental health and reduced use of emergency medical ser-
vices among those who were randomly assigned to
problem-solving therapy. This was associated with a dif-
ference of 3.6 (standard deviation (SD) = 6.9) in total
ZAN-BPD score.
The ZAN-BPD rating scale was also used to exam-
ine the clinical effectiveness of lamotrigine for people
with BPD in a randomized trial conducted by Reich
Table 1 Study assessment schedule
Assessments Screening Baseline 12-week
follow-up
24-week
follow-up
52-week
follow-up
Structured Clinical Interview
for DSM-IV Axis II Personality disorders
X----
Structured Clinical Interview
for DSM-IV (SCID-I)
a
X----
Hypomanic Checklist X - - - -
Alcohol, Smoking and Substance
Involvement Screening Test (ASSIST)
X---X
Morisky scale - - X X X
Zanarini Rating Scale for Borderline
Personality Disorder (ZAN-BPD)
- XXXX
Beck Depression Inventory - X X X X
Acts of Deliberate Self Harm - X X X X
Social Functioning Scale - X X X X
EuroQoL-5D - X X X X
Side Effect Scale - X X X X
Modified Adult Service
User Schedule
- XXXX
DSM-IV Diagnostic and Statistical Manual of Mental Disorders (4th edition), EuroQoL-5D European quality of Life-5 dimensions
a
Section on bipolar affective disorder (type I and II)
Crawford et al. Trials (2015) 16:308 Page 5 of 10
and colleagues [10]. In this small trial (n= 28), a
non-statistically significant difference in total score
(5.6, SD = 6.75) on the ZAN-BPD was found at 12
weeks. Seventeen people (61 %) in the trial completed
all 12 weeks of the study, and levels of adherence to
trial medications in those who completed the study
were judged to be high.
It is anticipated that levels of adherence to trial medi-
cations may be lower than in the study by Reich and col-
leagues, and the study has been powered on the basis of
a minimal clinically significant difference in ZAN-BPD
score of 3.0 (SD = 6.75). The sample size was calculated
by using Stata version 13 (StataCorp LP, College Station,
TX, USA).
Two hundred fourteen participants (107 receiving
lamotrigine and 107 receiving placebo) would need to be
randomly assigned to have 90 % power to detect a min-
imal clinically relevant difference of 3.0 (SD = 6.75) in
total score on the ZAN-BPD at 52 weeks by using a 0.05
two-sided level of statistical significance. To take ac-
count of 15 % loss to follow-up at 52 weeks, sample size
has been increased to 252.
Assignment of interventions
After consenting to participation and completing screen-
ing assessments, patients who are found to be eligible
will be randomly allocated to the intervention or com-
parator arm of the trial by the automated randomization
service operated by Nottingham Clinical Trials Unit.
Equal numbers of participants will be randomly assigned
to each arm of the trial. Stratification will occur by study
centre, severity of personality disorder (simple or com-
plex personality disorder according to criteria developed
by Tyrer and Johnson [13]), and extent of bipolarity
(using a score of more or less than 14 on the Hypomania
Checklist [15]).
Blinding
The randomization service will generate a unique trial
identification number for that participant, which will be
used on the case report forms (CRFs). Blinding of inves-
tigators, researchers, clinicians, and patients will be
maintained until all data entry and processing are
complete and the database has been locked. All patients,
carers, and study personnel will be blinded to treatment
assignment. The study statistician will also be blind to
trial arm allocation. Premature disclosure of allocation
runs the risk of introducing bias and invalidating the
trial results. Therefore, masking of treatment allocation
will be maintained during the course of the trial unless
the following occur: a serious adverse event arises that
clinically requires disclosure, a trial drug overdose that
requires disclosure occurs, or the participant becomes
pregnant.
In anticipation of an emergency, investigators, clini-
cians, and participants will be provided with the tele-
phone number for a 24-h emergency unblinding service
at the Medical Toxicology and Information Services,
which offers medical support. This system will allow a
medical request for unblinding in the event of a medical
emergency to be responded to 24 h a day, 7 days a week.
Procedures will be put in place to verify the identity of
the participant and caller, and the decision on whether
to reveal the study medication allocation will be based
on a set of criteria for judging clinical need. All requests
for unblinding will be recorded.
After the completion of the 52-week follow-up as-
sessment and regardless of whether they withdraw
from the study early or complete the participation
period in full, an email will be sent to the referring
psychiatrist informing them of the participant’strial
arm allocation. Where a participant has completed
the participation period in full, this will allow the pre-
scribertimetomakearrangementsfortheparticipant
to continue on lamotrigine if appropriate and desired.
Upon completion of their 52-week follow-up assess-
ment, the participant will be advised to contact their
psychiatrist to discuss their trial arm allocation if he
or she wishes to know whether they were taking the
active or placebo medication.
Study logistics
Recruitment
Potential participants will initially be approached
about the study by any health-care professional who
is involved in their care provided that the consultant
psychiatrist for the team has agreed in principle that
patients under their care may take part in the study.
If a psychiatrist or other health-care professional has a
patient under their care who they believe meets the eligi-
bility criteria for the study, they will introduce the patient
to the study at an appropriate time by briefly describing it
and provide an information sheet. The information sheet
will include an explanation of the exact nature of the trial,
the requirements of the protocol, any known adverse ef-
fects of the trial medicine, and any known risks involved
in taking part. It will be clearly stated that the patient is
free to withdraw from the trial at any time for any reason
without prejudice to future care and with no obligation to
give the reason for withdrawal.
The patient must provide verbal agreement to discuss
their eligibility and possible enrolment into the trial with
a member of the research team before any further step
in the study process can take place. If a patient does not
give verbal agreement to discuss their eligibility and pos-
sible enrolment into the trial, no further aspect of the
screening process will be carried out at that time. How-
ever, where a patient later decides that they are willing
Crawford et al. Trials (2015) 16:308 Page 6 of 10
to be considered for entry into the trial, previous refusal
does not preclude this. Where verbal agreement is given,
the patient will be assigned a screening number and
contacted by the research team to discuss consent.
Potential participants will be given no less than 24 h
from receiving the information sheet to consider the in-
formation and the opportunity to question the investiga-
tor, their general practitioner (GP), or other independent
parties regarding participation in the trial. Written in-
formed consent then will be obtained and will include
permission for the LABILE research team to notify the
patient’s GP and consultant (who may be the referring
psychiatrist) about the enrolment of their patient into
the trial. Additionally, the patient will be asked whether a
family member or friend can be contacted solely for the
purpose of helping the team to obtain follow-up data, for
which a separate written informed consent will be re-
quired. The patient will not be excluded from the study if
he or she does not give consent for the research team to
contact family members or friends. A copy of the signed
informed consent form(s) will be given to the patient and
their consultant. The original signed form(s) will be
retained at the trial site.
Screening and baseline
If consent is given and documented, a screening assess-
ment CRF will be completed with the participant. If the
participant fulfils the eligibility criteria, they will
complete the baseline assessment and be randomly
assigned. After randomization, the participant’s GP and
consultant will be informed of their enrolment into the
trial.
Follow-up
The 12-, 24-, and 52-week assessments (Table 1) will be
scheduled to coincide with the supplying of the partici-
pant’s study medication. Prior to preparing each new
prescription, the psychiatrist or researcher will contact
the participant to elicit details of any adverse events and
to ascertain whether they wish to continue with the trial.
If the participant continues to experience adverse
event(s), further monitoring will be performed even
when they are no longer being prescribed the study
medication. Further follow-up by visit or telephone call
will be arranged as required. All participants will be of-
fered a £20 honoraria after completion of the 52-week
follow-up interview.
Data management and analysis
Data will be entered onto a secure web-based data entry
system. Access will be restricted by user identifiers and
passwords (encrypted by using a one-way encryption
method). The database will be backed up daily in
encrypted form, and offsite copies will be made at
regular intervals. Study data will be archived securely
and then safely destroyed after 15 years. Analysis and
reporting of the trial will be in accordance with CON-
SORT (Consolidated Standards of Reporting Trials)
guidelines. Further details about the statistical analyses
will be provided in the statistical analysis plan which will
be finalised prior to completion of data collection, data-
base lock, and unblinding of the study.
Continuous variables will be summarised in terms of
the mean, SD, median, lower and upper quartiles, mini-
mum, maximum, and number of observations. Categor-
ical variables will be summarised in terms of frequency
counts and percentages. Descriptive statistics of demo-
graphic and clinical measures will be used to examine
balance between the randomized arms at baseline. The
primary approach to between-group comparisons will be
to analyse participants according to the group to which
they were allocated, regardless of treatment received,
and without imputation of missing outcome data. All
data will be analysed by using Stata version 13 or a later
version.
Appropriate descriptive statistics for ZAN-BPD score
will be reported for each randomly assigned group at
each scheduled follow-up time point. There are two pro-
posed analyses of ZAN-BPD data. For our primary ana-
lysis, ZAN-BPD score at 52-week follow-up, randomly
assigned groups will be compared by using a generalised
linear model for continuous outcome adjusted by base-
line ZAN-BPD score, centre, severity of personality dis-
order (simple or complex), and the extent of bipolarity
(score of at least 14 or of less than 14). The effective-
ness parameter comparing lamotrigine plus usual care
withusualcarealonewillbethedifferenceinmean
ZAN-BPD score at 52 weeks along with 95 % confi-
dence interval and exact Pvalue.
For our main secondary analysis, ZAN-BPD scores at
12, 24, and 52 weeks will be compared by using a mixed
model for repeated outcome measures adjusted by the
same stratification variables used for the primary ana-
lysis. We will investigate whether any treatment effects
were sustained or emerged later by including an inter-
action term between treatment group and time in the
model. In the absence of a time effect, the effective-
ness parameter will be the average difference in mean
ZAN-BPD score over the 52-week period along with
95 % confidence interval and exact Pvalue.
Sensitivity analyses will be conducted for both analyses
(i) to further adjust for any variable with marked imbal-
ance at baseline, (ii) to investigate the impact of missing
data by using multiple imputation, and (iii) to investigate
the effect of treatment adherence.
Analysis of secondary outcomes will follow a similar
approach by using appropriate mixed effects regression
models (for example, logistic for binary outcomes) (that
Crawford et al. Trials (2015) 16:308 Page 7 of 10
is, comparison at both 52-week follow-up and by using
repeated measures analysis of follow-up data collected at
12, 26, and 52 weeks).
Health economic analysis
The economic evaluation will take the NHS/Personal
Social Services perspective preferred by the National
Institute for Health and Clinical Excellence [31] and
shown to be the key cost sector in previous research
among people with BPD [29]. Data on the use of
health and social services will be collected by using a
modified version of the Adult Service Use Schedule
adapted for use in this population on the basis of
previous research in this area [29]. The cost of lamo-
trigine will be calculated by using the generic cost
listed in the British National Formulary and the cost
of the time with the dispensing clinician by using na-
tional UK unit costs. National UK unit costs will be
applied to medication, hospital contacts, and commu-
nity health and social services [32, 33].
Differences in mean costs will be analysed by using
standard parametric ttests with the validity of results
confirmed by using bias-corrected, non-parametric boot-
strapping (repeat re-sampling) [34]. Despite the skewed
nature of cost data, this approach is recommended to
enable inferences to be made about the arithmetic mean
[35]. Cost-effectiveness will be assessed through the cal-
culation of incremental cost-effectiveness ratios [36] and
will be explored in terms of cost utility by using quality-
adjusted life-years derived from the EuroQoL-5D and
cost-effectiveness by using the ZAN-PD. Uncertainty
around the cost and effectiveness estimates will be rep-
resented by cost-effectiveness acceptability curves [37].
All analyses of cost will be adjusted for baseline stratifi-
cation variables and baseline costs.
Data monitoring
The project will be overseen by a trial steering commit-
tee (TSC) made up of a representative of the project
funder and independent representatives of service users
and providers. An Independent Data Monitoring and
Ethics Committee will monitor recruitment of study par-
ticipants, ethical issues of consent, quality of data (in-
cluding missing data), the incidence of adverse events,
and any other factors that might compromise the pro-
gress and satisfactory completion of the trial. The group
will have access to unblinded data if requested. It will be
chaired by an independent academic and report to the
TSC.
Day-to-day running of the project will be overseen by a
trial management group. The role of the group will be to
monitor all aspects of the conduct and progress of the
trial, ensure that the protocol is adhered to, and take ap-
propriate action to safeguard participants and the quality
of the trial itself. The group will act in accordance with de-
cisions made by the TSC. People with experience using
services will be represented on the TSC and contribute to
the design, conduct, and reporting of study findings.
Ethics
Approval for the research was given by the London Cen-
tral Research Ethics Committee (reference number 12/
LO/1514) and by the Research and Development depart-
ments of the participating NHS Trusts. We will ensure
that the trial is conducted in full conformity with the
current revision of the Declaration of Helsinki (last
amended October 2000, with additional footnotes added
2002 and 2004) and with the Medicines for Human Use
(Clinical Trials) Regulation 2004 transposed into law
from the EU Clinical Trials Directive 2001/20/EC, the
EU Good Clinical Practice Directive 2005, and all
current and future acts and requirements pertaining to
its conduct.
Each study participant will be assigned a unique trial
identification number at the start of the assessment
process. This number will be written on all clinical as-
sessment forms/datasheets and databases used to record
data on study participants. A hard copy of a record sheet
linking patient identity, contact details, and trial identifi-
cation number for all participants will be kept at each
site. It will be placed in the investigator site file, in a
locked filing cabinet, separate from the paper CRFs and
other documents relating to a participant, which will be
anonymised. Recorded data will be entered onto an elec-
tronic data management system that will use the trial
identification number rather than the participant’s name
or other information that could identify them.
Discussion
The LABILE trial will be the first study to examine the
long-term clinical effectiveness and cost-effectiveness of
lamotrigine for people with BPD. As such, the trial has
the potential to help guide prescribers and patients when
deciding whether this drug could help reduce the dis-
tress they experience and improve their quality of life.
Current guidance from the National Institute for
Health and Care Excellence states that drug treatments
should “not be used for BPD or for the individual symp-
toms or behaviour associated with the disorder”[38].
This position was endorsed by subsequent guidance is-
sued by the National Health and Medical Research
Council in Australia [39] but contrasts with earlier
American guidelines which state that mood stabilizers
should be considered as a second-line treatment for
affective dysregulation in patients with BPD [40]. The need
for further trials of pharmacological treatments for people
with borderline personality was highlighted in a Cochrane
systematic review in 2008 [41]. Previous reports have
Crawford et al. Trials (2015) 16:308 Page 8 of 10
highlighted the uncertainty that prescribers currently ex-
perience when considering whether to use pharmacological
approaches to help people with BPD [42], and we believe
that this trial can help reduce some of this uncertainty.
Strengths of the LABILE study are that it has a clear
primary hypothesis based on an outcome measure which
assesses core features of BPD. As BPD is a long-term
condition and previous placebo-controlled trials have ex-
amined outcomes only over 8 to 12 weeks, we want to
examine the longer-term effects of offering people this
treatment. For this reason, our primary outcome meas-
ure is score on the ZAN-BPD at 52 weeks. However,
BPD is also a fluctuating condition, and it is possible
that patients may derive some benefit from treatment
even if these are not seen at 52 weeks. For this reason,
the first of our secondary outcomes is symptoms of BPD
over the 52 weeks after randomization using repeated
measures analysis of data collected at 12-, 26-, and 52-
week follow-up. This measure will allow us to examine
whether patients who are offered lamotrigine have im-
proved mental health in the year after they are first of-
fered this treatment.
Other strengths are that we are recruiting participants
from a broad range of secondary care mental health ser-
vices and we have limited our exclusion criteria with the
aim of generating findings that are generalisable across
the NHS in England and in other countries with similar
health-care systems. Finally, the study is collecting de-
tailed information about resource use and other costs
that will enable us to conduct a high-quality economic
evaluation of the impact of adding lamotrigine to usual
care of people with BPD.
This trial faces a number of challenges which will need
to be overcome if we are to recruit to target. In addition
to pressures of workload and other factors that may
deter clinicians from referring people to clinical trials,
clinicians may be concerned about the impact of the trial
on what can sometimes be strained relationships with
patients. National guidance on the treatment of people
with BPD in England advises against the use of pharma-
cological treatments and this may deter some clinicians
from referring people to the study. Potential participants
may be concerned about being asked to take part in a
study in which they might be allocated to an inert pla-
cebo for a 12-month period. In an attempt to overcome
these obstacles, we have developed information for clini-
cians that emphasises the extent of off-label prescribing
of psychotropic medication for people with personality
disorder and reminds them that national guidance is
based on the relative absence of evidence rather than
evidence of lack of effect. Initial discussions with poten-
tial participants suggest that many recognise the limita-
tions of current treatment options and that there is
considerable interest in taking part in the study.
We have previously concluded that existing evidence is
insufficient to recommend the use of lamotrigine or other
mood stabilizers in clinical practice [42]. The LABILE
study has the potential to reduce this uncertainty by gen-
erating high-quality evidence on the impact of adding this
drug to the usual care that patients receive over the course
of a 12-month period.
Trial status
Recruitment is ongoing (218 participants recruited as of
end of May 2015).
Abbreviations
BPD: Borderline personality disorder; CRF: Case report form;
EuroQoL-5D: European quality of Life-5 dimensions; GP: General practitioner;
LABILE: Lamotrigine and borderline personality disorder: Investigating
Long-term effectiveness; NHS: National Health Service; SCID-II: Structured
Clinical Interview for Axis II Personality Disorders; SD: Standard deviation;
TSC: Trial steering committee; ZAN-BPD: Zanarini rating scale for borderline
personality disorder.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
MJC is the chief investigator on the study and contributed to the design of
the study, the study protocol, and preparation of this manuscript. RS
provides clinical leadership, recruits and follows up study participants, and
contributed to the design of the study protocol and preparation of this
manuscript. BB developed plans for the economic evaluation and
contributed to the design of the study, the study protocol, and preparation
of this manuscript. SB assisted with the developed plans for the economic
evaluation and contributed to the preparation of this manuscript. GC and GL
recruit and follow up study participants and contributed to the development
of this manuscript. KG contributed to the design of the study protocol. GL-S
is a principal investigator. VL coordinates the trial and contributed to the
development of the study protocol and preparation of this manuscript. FL
coordinates service user involvement in the study and contributed to the
design of the study protocol. AM and WT contributed to the development
analysis plan for the study, the study protocol, and the preparation of this
manuscript. RM and JGR are principal investigators and contributed to the
design of the study, the study protocol, and preparation of this manuscript.
CP is the lead pharmacist on the project and contributed to the design of the
study, the study protocol, and preparation of this manuscript. PT contributed to
the design of the study, the study protocol, and preparation of this manuscript.
All authors read and approved the final manuscript.
Acknowledgments
This research is supported by funding from the National Institute for Health
Research Health Technology Assessment Programme (reference number 10/
103/01). Results will be published in full in the Health Technology
Assessment journal series. The views and opinions expressed herein are
those of the authors and do not necessarily reflect those of the funder.
Additional support was provided to the study through the Imperial National
Institute for Health Research Biomedical Research Centre. RM is funded in
part through the National Institute for Health Research Collaboration for
Leadership in Applied Health Research and Care East Midlands.
Author details
1
Centre for Mental Health, Imperial College London, Du Cane Road, London
W12 ONN, UK.
2
King’s Health Economics, King’s College London, De
Crespigny Park, London SE5 8AF, UK.
3
School of Medicine, Pharmacy and
Health, Durham University, Stockton Road, Durham DH1 3LE, UK.
4
Oxleas
NHS Foundation Trust, Pinewood Place, Dartford DA2 7WG, UK.
5
Faculty of
Medicine & Health Sciences, University of Nottingham, Queen’s Medical
Centre, Nottingham NG7 2UH, UK.
Crawford et al. Trials (2015) 16:308 Page 9 of 10
Received: 2 March 2015 Accepted: 26 June 2015
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