Clozapine in the treatment of borderline personality disorder. The CALMED study.
| ISRCTN | ISRCTN18352058 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18352058 |
| EudraCT/CTIS number | 2018-002471-18 |
| Secondary identifying numbers | 39949 |
- Submission date
- 18/03/2019
- Registration date
- 26/03/2019
- Last edited
- 09/08/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
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?
Dr Verity Leeson, v.leeson@imperial.ac.uk
Contact information
Scientific
Centre for Psychiatry
Imperial College
7th Floor Commonwealth Building
Du Cane Road
London
W12 0NN
United Kingdom
| Phone | +44 (0)208 383 4767 |
|---|---|
| v.leeson@imperial.ac.uk |
Study information
| Study design | Interventional randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN18352058_PIS_v3_01May19.pdf |
| Scientific title | The clinical effectiveness and cost effectiveness of clozapine for inpatients with borderline personality disorder: randomised controlled trial |
| Study acronym | CALMED |
| Study objectives | 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(s) | 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 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | 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 study start date | 01/06/2019 |
| Completion date | 31/07/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 222; UK Sample Size: 222 |
| Total final enrolment | 29 |
| Key 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 (added 08/01/2020) 7. Have been an inpatient on a mental health ward for more than 28 days in the last 12 months, OR have had two or more admissions to hospital/ periods of care provided by Home Treatment over the last 12 months, AND a lifetime history of two or more incidents of harm to self or others which resulted in permanent damage/ disability, or would have done so had services not intervened |
| Key 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 and it is not possible to continue the necessary monitoring of physical health as an outpatient (updated 21/08/2019, previously: 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 |
| Date of first enrolment | 01/09/2019 |
| Date of final enrolment | 04/03/2021 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
St Pancras Hospital
4 St Pancras Way
London
NW1 0PE
United Kingdom
1 Armstrong Way
Southall
London
UB2 4SD
United Kingdom
Kings Business Park
Prescot
L34 1PJ
United Kingdom
Fulwood
Preston
PR2 8DW
United Kingdom
Porchester Road
Mapperley
Nottingham
NG3 6AA
United Kingdom
off Saxon Street
Eaglestone
Milton Keynes
MK6 5LT
United Kingdom
Northampton
NN1 5DG
United Kingdom
Sponsor information
University/education
Joint Research Compliance Office [JRCO]
Imperial College London
Room 221
Medical School Building
St Mary’s Campus
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | 020 7594 9480 |
|---|---|
| g.pereira-barreto@imperial.ac.uk | |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/10/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Mike Crawford (m.crawford@imperial.ac.uk). 1. Type of data that will be shared: de-identified participant-level data including primary and secondary outcome measures, and adverse events. 2. When the data will become available and for how long: from 01/01/2022 with no fixed end date 3. By what access criteria data will be shared including with whom, for what types of analyses, and by what mechanism: data may be accessed by researchers who provide a methodologically sound proposal by email to Prof. Crawford 4. Whether consent from participants was obtained: all participants gave written informed consent 5. Comments on data anonymisation: any data that could potentially be used to identify participants will not be provided in the dataset at the individual participant level e.g. ethnicity, dates of service use |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v3 | 01/05/2019 | 29/10/2019 | No | Yes |
| Participant information sheet | version v4 | 26/12/2019 | 08/01/2020 | No | Yes |
| Participant information sheet | version v5.0 | 11/02/2020 | 15/07/2020 | No | Yes |
| Protocol file | version v9 | 08/12/2020 | 04/03/2021 | No | No |
| Statistical Analysis Plan | version v2 | 08/07/2021 | 22/07/2021 | No | No |
| Results article | 29/04/2022 | 09/08/2022 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN18352058_PIS_v3_01May19.pdf
- uploaded 29/10/2019
- ISRCTN18352058_PIS_v4_26Dec19.pdf
- uploaded 08/01/2020
- ISRCTN18352058_PIS_v5.0_11Feb2020.pdf
- uploaded 15/07/2020
- ISRCTN18352058_PROTOCOL_v9_08Dec20.pdf
- uploaded 04/03/2021
- ISRCTN18352058_SAP_V2_08Jul21.pdf
Editorial Notes
09/08/2022: Publication reference added.
22/07/2021: Uploaded statistical analysis plan.
21/05/2021: IPD sharing statement added.
08/04/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/03/2021 to 04/03/2021.
2. The overall trial end date was changed from 31/03/2021 to 31/07/2021.
3. The intention to publish date was changed from 01/09/2023 to 01/10/2021.
4. Total final enrolment number added.
04/03/2021: Uploaded protocol (not peer-reviewed) as an additional file. Version 9, 8 December 2020.
15/07/2020: The following changes were made to the trial record:
1. The recruitment resumed.
2. The participant information sheet v5.0 was uploaded as an additional file.
17/04/2020: Due to current public health guidance, recruitment for this study has been paused.
09/03/2020: The following changes were made to the trial record:
1. The scientific contact was changed.
2. The plain English summary was updated to reflect these changes.
08/01/2020: The following changes were made to the trial record:
1. An updated participant information sheet was uploaded as an additional file.
2. The inclusion criteria were updated.
29/10/2019: The participant information sheet was uploaded as an additional file.
26/09/2019: The plain English summary was updated to reflect the change in the scientific contact.
27/08/2019: Internal review.
21/08/2019: The following changes were made to the trial record:
1. The exclusion criteria were changed.
2. The scientific contact was changed from Leeson, Verity <v.leeson@imperial.ac.uk> to Claringbold, Amy <a.claringbold@imperial.ac.uk>.
