Condition category
Mental and Behavioural Disorders
Date applied
18/03/2019
Date assigned
26/03/2019
Last edited
26/03/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
People with borderline personality disorder experience rapid and distressing changes in mood and difficulties in their relationships with others. These problems can lead to impulsive aggression, deliberate self-harm and suicide. People with borderline personality disorder are often given medication, but no drugs are licensed for this condition. In recent years doctors have tried using ‘clozapine’, an antipsychotic drug which is effective in treating other mental health conditions. There have been reports that it can improve mental health of inpatients with borderline personality disorder, but the drug has serious side effects which can be life-threatening and no clinical trials have been conducted.

Who can participate?
We will recruit people aged 18 years or over who are inpatients, have a confirmed diagnosis, and have failed to make an adequate response to existing treatment despite taking other antipsychotic drugs for at least three months. We will exclude people who have a clinical diagnosis of psychosis and those already taking clozapine.

What does the study involve?
We plan to conduct a randomised trial to examine the clinical and cost-effectiveness of clozapine versus placebo for inpatients with borderline personality disorder. We will recruit 222 people from inpatient services across England. At the start of the study we will assess patients’ mental health, self-harm, aggressive behaviour, health-related quality of life, side effects of treatment and costs of care. Each person in the study would have an equal chance of receiving clozapine or placebo in addition to the care they would normally receive. Researchers will conduct follow-up assessments at three and six months, and will not know whether people are being prescribed clozapine or the placebo.

What are the possible benefits and risks of participating?
By taking part in this study, participants with will help us find out whether clozapine helps to improve the mental health of people who suffer from borderline personality disorder, and whether it reduces the time people spend in hospitals. As with any medicine, side effects are possible with clozapine, however, not everyone who takes the medication will experience problems. Another disadvantage is that patients will be asked to give blood on weekly basis for 18 weeks, and then every two weeks for the following 14 weeks. To reduce the risk of side effects, patients will receive a low dose of the study medication which is increases slowly. The most serious side effect of clozapine is agranulocytosis and for this reason, patients are required to have regular blood tests.

Where is the study run from?
Imperial College London

When is the study starting and how long is it expected to run for?
August 2019, 36 months

Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC)

Who is the main contact?
Izabela Eberhart, i.eberhart@imperial.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Ms Verity Leeson

ORCID ID

http://orcid.org/0000-0001-7548-8096

Contact details

Imperial College London
7th Floor Commonwealth Building
Du Cane Road
London
W12 0NN
United Kingdom
0208 383 4767
v.leeson@imperial.ac.uk

Additional identifiers

EudraCT number

2018-002471-18

ClinicalTrials.gov number

Nil known

Protocol/serial number

39949

Study information

Scientific title

The clinical effectiveness and cost effectiveness of clozapine for inpatients with borderline personality disorder: randomised controlled trial

Acronym

CALMED

Study hypothesis

The study primary hypothesis is that, for inpatients with borderline personality disorder, the addition of clozapine to usual treatment reduces symptoms of the disorder measured using the Zanarini Rating scale for Borderline Personality Disorder (ZAN- BPD).

Ethics approval

Approved 18/12/2018, Wales Research Ethics Committee 1 (Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB; 02920 785738; jagit.sidhu@wales.nhs.uk), ref: 18/WA/0382

Study design

Interventional randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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

Condition

Borderline personality disorder

Intervention

Study participants in the active arm of the trial will be prescribed a dose of up to 400mg of clozapine daily, depending on clinical response, patient preference and side effects.
Those in the control arm of the trial will be prescribed equivalent numbers of placebo capsules. All those taking part in the study will continue to receive all other treatments as usual.
All study participants will be monitored in the same way regardless of the treatment arm they are in. There are three components to assessing and monitoring the health of people prescribed clozapine: full blood counts, monitoring of short term adverse events and long-term side effects of the drug physical health monitoring during initiation of treatment and continuing during trial treatment.

Remote web-based randomisation will be undertaken through a fully automated service operated by the NWORTH, University of Bangor. Randomisation will be via a secure online system using a sequentially randomised dynamic adaptive algorithm stratified by centre, ward type (general adult, low secure, medium secure and high secure) and gender (male or female). Within the algorithm, the likelihood of the participant being allocated to each treatment group is recalculated based on the participants already recruited and allocated. This recalculation is done at the overall allocation level, within stratification variables and within stratum level. By undertaking this re-calculation, the algorithm ensures that balance is maintained within acceptable limits of the assigned allocation ratio while maintaining unpredictability.

Intervention type

Drug

Phase

Not Specified

Drug names

Clozapine

Primary outcome measure

Total score on the Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) at six months (primary end point)

Secondary outcome measures

1. Total score on the Zanarini rating scale for Borderline Personality Disorder at three months.
2. General mental health using the Brief Psychiatric Rating Scale (BPRS) at three and six months.
3. Incidence and severity of suicidal behaviour using the Acts of Deliberate Self-Harm Inventory.
4. Level of aggressive behaviour using the Modified Overt Aggression Scale
5. Health related quality of life using the EQ-5D-5L.
6. Side effects of medication using the Antipsychotic Non-Neurological Side Effects Scale (ANNSERS) and motor and extrapyramidal side effects using the Extrapyramidal Side Effects Scale.
7. Incidence of withdrawal of trial medication due to adverse effects.
8. Medication adherence at three and six months using the Brief Adherence Rating Scale.
9. Resource use collected using a modified version of the Adult Service Use Schedule and by examining clinical records at six, 12 and 18 months. This will include detailed information about length of inpatient treatment and type of ward (high, medium, low secure, Psychiatric Intensive Care, general adult etc.), contacts with community mental health services and emergency medical services, and the type and dose of psychotropic medication that people are prescribed.

Overall trial start date

01/06/2019

Overall trial end date

31/03/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged 18 years or over
2. Currently an inpatient on a mental health unit
3. Meeting DSM-IV diagnostic criteria for borderline personality disorder
4. Failure to make an adequate clinical response to taking antipsychotic medication other than clozapine for at least three months
5. Satisfactory pre-treatment full blood count (white blood cell count > = 3.5 and absolute neutrophil count > = 2.0)
6. Weight and blood glucose recorded in their clinical records

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 222; UK Sample Size: 222

Participant exclusion criteria

1. Current clinical diagnosis of schizophrenia, or bipolar I disorder
2. Prescribed clozapine within the last two weeks
3. Pregnant, trying to conceive, breastfeeding, or a woman of childbearing potential and is not using a highly
effective birth control.
4. Due to be discharged from the unit within the following two weeks
5. Unable to speak sufficient English to complete the baseline assessment
6. Unwilling or unable to provide written informed consent to take part in the study
7. Unable to undergo regular blood tests
8. Contraindication to clozapine or other listed condition, namely:
9. Known history of primary bone marrow disorders or impaired bone marrow function
10. Severe renal or cardiac disorders (e.g. myocarditis), or a known history of cardiac illness or abnormal cardiac findings on physical examination
11. Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
12. Hypersensitivity to: Magnesium stearate; Silica, colloidal anhydrous; Povidone K30; Talc; Maize starch; Lactose monohydrate
13. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy)
14. History of clozapine-induced agranulocytosis
15. Uncontrolled epilepsy
16. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions
17. Circulatory collapse and/or CNS depression of any cause
18. Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure
19. Paralytic ileus

Recruitment start date

01/09/2019

Recruitment end date

31/03/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Central and North West London NHS Foundation Trust
1st Floor Bloomsbury Building St Pancras Hospital 4 St Pancras Way
London
NW1 0PE
United Kingdom

Trial participating centre

West London Mental Health NHS Trust
1st Floor, Wing B 1 Armstrong Way Southall
London
UB2 4SD
United Kingdom

Trial participating centre

Merseycare NHS Foundation Trust
Trust Headquarters Kings Business Park
Prescot
L34 1PJ
United Kingdom

Trial participating centre

Lancashire Care NHS Foundation Trust
Vicarage Lane Fulwood
Preston
PR2 8DW
United Kingdom

Trial participating centre

Nottinghamshire Healthcare NHS Foundation Trust
Duncan MacMillan House Porchester Road Mapperley
Nottingham
NG3 6AA
United Kingdom

Trial participating centre

Elysium Healthcare
Chadwick Drive off Saxon Street Eaglestone
Milton Keynes
MK6 5LT
United Kingdom

Trial participating centre

St Andrew’s Healthcare
Cliftonville
Northampton
NN1 5DG
United Kingdom

Sponsor information

Organisation

Imperial College of Science, Technology and Medicine

Sponsor details

Joint Research Compliance Office [JRCO]
Imperial College London
Room 221
Medical School Building
St Mary’s Campus
Norfolk Place
London
W2 1PG
United Kingdom
020 7594 9480
g.pereira-barreto@imperial.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

We will use a broad range of methods to communicate the results of this research to all stakeholders including both those who provide and use mental health services for people with BPD. This will include written reports, presentations at conferences, social media, a webinar, and communications with NICE, service user groups and professional bodies. We will publish our findings in the Health Technology Assessment Journal and in widely read high-quality peer-reviewed open access journals. We will present the results of the study at the leading conferences for personality disorder and those for mental health nurses and pharmacists: the Annual Conference of the British and Irish Group for the Study of Personality Disorder, the Annual Congress of the Royal College of Psychiatrists, the Forensic Faculty of the Royal College of Psychiatrists, the Summer Meeting of the Royal College of Nursing, and the annual meeting of the College of Mental Health Pharmacy.

IPD sharing statement:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request

Intention to publish date

01/09/2023

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes