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Clinical Trial Results:
Lamotrigine And Borderline Personality Disorder: Investigating Long-Term Effectiveness

Summary
EudraCT number	2012-003136-23
Trial protocol	GB
Global end of trial date	22 Sep 2016

Results information
Results version number	v1(current)
This version publication date	07 Sep 2017
First version publication date	07 Sep 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CRO1990

ISRCTN number

ISRCTN90916365

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Imperial College London

Sponsor organisation address

Faculty of Medicine, London, United Kingdom, SW7 2AZ

Public contact

Clinical Trials Office, Imperial College London, 44 2073861220, v.leeson@imperial.ac.uk

Scientific contact

Clinical Trials Office, Imperial College London, 44 2073861220, v.leeson@imperial.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Nov 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Sep 2016

Global end of trial reached?

Yes

Global end of trial date

22 Sep 2016

Was the trial ended prematurely?

Main objective of the trial

The main objectives of the study are as follows: i. To test whether adding lamotrigine to usual care for adults with borderline personality disorder (BPD) improves mental health over a 52 week period, in comparison to a placebo control. ii. To examine whether the addition of lamotrigine to usual care for adults with BPD improves social functioning and quality of life, reduces the incidence of suicidal behaviour, and lowers the amount of antipsychotic and other psychotropic medication that people are prescribed, in comparison to a placebo control. iii. To compare the incidence of side effects among those prescribed lamotrigine in addition to usual care for adults with BPD, in comparison to a placebo control. iv. To examine the cost, cost-utility and cost-effectiveness of adding lamotrigine to usual care for adults with BPD, in comparison to a placebo control.

Protection of trial subjects

Thorough monitoring of adverse events and participant wellbeing occurred as part of the assessment process. During assessment and testing breaks were provided to minimise possible fatigue or stress, and if indicated, the assessment were spread over more than one visit.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jun 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 276

Worldwide total number of subjects

276

EEA total number of subjects

276

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

276

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

-Age 18+. -Fulfills DSM-IV diagnostic criteria for BPD. -Does not fulfil criteria for Bipolar affective disorder (type I & II), or psychotic disorder -Receiving a mood stabiliser -Medical history of liver or kidney impairment. -Cognitive or language difficulties. -Pregnant, planning a pregnancy or not using adequate contraception.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Are arms mutually exclusive

Yes

lamotrigine

Arm description

Arm type

Experimental

Investigational medicinal product name

lamotrigine

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

For those not taking a combined hormonal contraceptive, the starting dose will be 25mg per day. Depending on the response and tolerance it will be increased to 50mg after two weeks, 100mg after four weeks and 200mg thereafter. If there are problems with tolerability at 200mg, the clinician can reduce the dose back to 100mg/day. For those who are taking a combined hormonal contraceptive the starting dose will be 25mg per day. This will be increased to 50mg after two weeks, 100mg after four weeks, 200mg after six weeks, 300mg after eight weeks, and 400mg after ten weeks (see example (b) below). If there are problems with tolerability at 400mg, the clinician can reduce the dose back to 200 or 100 mg/day. Where a participant misses five or more consecutive days of the medication at any time during their participation dose titration will be restarted.

placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administration was matched to the active (lamotrigine) arm.

Number of subjects in period 1	lamotrigine	placebo
Started	137	139
Completed	97	98
Not completed	40	41
Adverse event, serious fatal	-	3
Consent withdrawn by subject	14	12
Adverse event, non-fatal	4	1
Other	6	5
Lost to follow-up	16	20

Baseline characteristics

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Reporting group title

lamotrigine

Reporting group description

Reporting group title

placebo

Reporting group description

Reporting group values	lamotrigine	placebo	Total
Number of subjects	137	139	276
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	36 ± 11	36.2 ± 11	-
Gender categorical
Units: Subjects
Female	103	105	208
Male	34	34	68

End points

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Reporting group title

lamotrigine

Reporting group description

Reporting group title

placebo

Reporting group description

Primary: ZAN-BPD

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End point title

ZAN-BPD

End point description

End point type

Primary

End point timeframe

52 week assessment

End point values	lamotrigine	placebo
Number of subjects analysed	97	98
Units: rating
arithmetic mean (standard deviation)	11.3 ± 6.6	11.5 ± 7.7

ZAN-BPD score at 52 weeks

Statistical analysis description

For primary analysis of ZAN-BPD score at 52 weeks follow up, randomised groups will be compared using a generalised linear model for continuous outcome adjusted by baseline ZAN-BPD score, centre, severity of personality disorder (simple or complex) and the extent of bipolarity (score >=14 or <14). The effectiveness parameter comparing lamotrigine plus usual care with usual care alone will be the difference in mean ZAN-BPD score at 52 weeks along with 95% confidence interval and exact p value.

Comparison groups

lamotrigine v placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.906

Method

generalised linear model

Parameter type

adjusted difference in mean

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

Adverse events

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Timeframe for reporting adverse events

8 July 2013 to 22 Sept 2016

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

lamotrigine

Reporting group description

Reporting group title

placebo

Reporting group description

Serious adverse events	lamotrigine	placebo
Total subjects affected by serious adverse events
subjects affected / exposed	26 / 137 (18.98%)	32 / 139 (23.02%)
number of deaths (all causes)	0	3
number of deaths resulting from adverse events
Surgical and medical procedures
Cholesystectomy
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Induced abortion
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Pregnancy
subjects affected / exposed	2 / 137 (1.46%)	3 / 139 (2.16%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Cyst
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 137 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Social circumstances
Recreational drug use
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Agitated
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Deliberate self-harm
subjects affected / exposed	4 / 137 (2.92%)	4 / 139 (2.88%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Emotional distress
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intentional overdose
subjects affected / exposed	11 / 137 (8.03%)	6 / 139 (4.32%)
occurrences causally related to treatment / all	0 / 12	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Mental distress
subjects affected / exposed	2 / 137 (1.46%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic episode
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal behaviour
subjects affected / exposed	5 / 137 (3.65%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	3 / 137 (2.19%)	5 / 139 (3.60%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal intention
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 137 (0.73%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoughts of self-harm
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Violent ideation
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Foot fracture
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intentional drug misuse
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	3 / 137 (2.19%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Photophobia
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Crohns disease aggravated
subjects affected / exposed	2 / 137 (1.46%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomitting
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Kidney function abnormal
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
painful arm
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess on buttock
subjects affected / exposed	1 / 137 (0.73%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Allergic reaction
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 137 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	lamotrigine	placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	77 / 137 (56.20%)	93 / 139 (66.91%)
Injury, poisoning and procedural complications
Bruising
subjects affected / exposed	10 / 137 (7.30%)	0 / 139 (0.00%)
occurrences all number	13	0
Intentional overdose
subjects affected / exposed	14 / 137 (10.22%)	9 / 139 (6.47%)
occurrences all number	15	11
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 137 (2.92%)	9 / 139 (6.47%)
occurrences all number	5	9
Headache
subjects affected / exposed	8 / 137 (5.84%)	5 / 139 (3.60%)
occurrences all number	8	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	15 / 137 (10.95%)	10 / 139 (7.19%)
occurrences all number	19	11
Nausea
subjects affected / exposed	8 / 137 (5.84%)	6 / 139 (4.32%)
occurrences all number	10	6
Vomitting
subjects affected / exposed	9 / 137 (6.57%)	7 / 139 (5.04%)
occurrences all number	10	7
Skin and subcutaneous tissue disorders
Skin rash
subjects affected / exposed	11 / 137 (8.03%)	11 / 139 (7.91%)
occurrences all number	13	11
Psychiatric disorders
Deliberate Self-Harm
subjects affected / exposed	8 / 137 (5.84%)	7 / 139 (5.04%)
occurrences all number	8	8
Suicidal ideation
subjects affected / exposed	4 / 137 (2.92%)	8 / 139 (5.76%)
occurrences all number	7	11

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Were there any global substantial amendments to the protocol? Yes

03 Jun 2013

1. The addition of the International Personality Disorder Examination (IPDE) at screening. 2. The addition of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) assessment at the 52 week follow-up assessment. 3. The wording in the protocol of “combined oral contraceptive pill” has been replaced by “combined hormonal contraceptive” 4. Additional information pertaining to trial medication supply added to the protocol. 5. Additional information pertaining to dispensing and accountability added to the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results:
Lamotrigine And Borderline Personality Disorder: Investigating Long-Term Effectiveness

Trial information

Trial information

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Subject disposition

Baseline characteristics

Baseline characteristics

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End points

Primary: ZAN-BPD

Primary: ZAN-BPD

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Adverse events

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Clinical Trial Results: Lamotrigine And Borderline Personality Disorder: Investigating Long-Term Effectiveness

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: ZAN-BPD

Primary: ZAN-BPD

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Lamotrigine And Borderline Personality Disorder: Investigating Long-Term Effectiveness