Investigating the use of clozapine in young people with psychosis
| ISRCTN | ISRCTN37176025 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN37176025 |
| EudraCT/CTIS number | 2021-006248-28 |
| IRAS number | 1004947 |
| Secondary identifying numbers | IRAS 1004947, CPMS 53859 |
- Submission date
- 10/08/2022
- Registration date
- 16/11/2022
- Last edited
- 24/04/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Mental and Behavioural Disorders
Plain English Summary
Background and study aims
Schizophrenia is a condition that causes symptoms like delusions, hallucinations, reduced motivation and muddled thinking. Schizophrenia usually starts in the twenties but can begin earlier, when it is often more severe. The main treatment is antipsychotic medication; if untreated, symptoms typically continue for many years. One antipsychotic, clozapine, works better than any other and has the best chance of working if started early on in treatment. On the other hand, clozapine has more side effects than some other antipsychotics, so doctors only use it when other drugs haven't helped. For this reason, almost all research on clozapine was done with adults who had already taken other antipsychotics. Research in children and young people with schizophrenia shows that antipsychotics do help them, but there is little research focussed on clozapine. Three studies suggest that clozapine works better than other antipsychotics in children and young people, but the studies were too small to be conclusive and doctors still don’t use it often, leading to enduring symptoms. Therefore we will study clozapine as a treatment for schizophrenia in young people, recruiting only people <25 years old and trying to recruit as many as possible aged <18 years.
Who can participate?
People <25 years old and trying to recruit as many as possible aged <18. We will include 260 people, recruited across various hospital clinics and services within the UK, who are still symptomatic after treatment with at least two antipsychotics.
What does the study involve?
A computer will decide randomly whether each person will take clozapine or any other antipsychotic for 12 weeks. Researchers will assess their symptoms several times without knowing which drug they are taking to avoid biases. At the end of the study, towards the end of 2026, we will see if clozapine reduced people’s symptoms more than other antipsychotics, their side effects, how well they feel, how much their treatment costs and how often they need hospital treatment. After the study is over, we will contact them again to see how they are doing in the longer term.
Some participants in the clinical trial will additionally be asked to complete a magnetic resonance imaging (MRI) brain scan and provide a blood sample, once at the beginning and once at the end of the twelve-week period. The MRI scans will be used to measure glutamate and related aspects of brain structure and function. The blood samples will be used to measure proteins in the blood involved in inflammation, such as cytokines. At the end of the study, we will see if the biological measures in the brain and blood change more during treatment with clozapine compared to other antipsychotics, and how they relate to the amount that symptoms improve.
What are the possible benefits and risks of participating?
Benefits:
Not provided at time of registration
Risks:
People with schizophrenia are routinely treated with antipsychotic medication as part of their usual care, and the participants will also be treated with antipsychotic - it is only the choice of antipsychotic that will be determined by the trial. The potential risks and burdens for research participants will thus be the same as standard care. To minimise side effects, clinicians will have complete freedom to adjust the dose to achieve the best balance between therapeutic and adverse effects. Treatment to combat side effects can also be given to participants in the same way as with usual care. Advice to prevent common side effects such as weight gain and sedation will be given at the beginning of the trial. Participants might not respond to treatment. Nonetheless, after the first 12 weeks of trial, treatment can be changed while remaining in the study for longer-term outcome.
Where is the study run from?
King’s College London (UK)
When is the study starting and how long is it expected to run for?
August 2022 to February 2027
Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).
Who is the main contact?
Dr James MacCabe, james.maccabe@kcl.ac.uk
Laura Marchant, Laura.marchant@kcl.ac.uk
Prof. Alice Egerton (embedded mechanistic study), Alice.Egerton@kcl.ac.uk
Contact information
Scientific
16 De Crespigny Park
London
SE5 8AB
United Kingdom
| Phone | +44 20 71885732 |
|---|---|
| clear@kcl.ac.uk |
Principal Investigator
16 De Crespigny Park
London
SE5 8AB
United Kingdom
| Phone | +44 207 848 0757 |
|---|---|
| james.maccabe@kcl.ac.uk |
Scientific
Department of Psychosis Studies
Institute of Psychiatry, Psychology and Neuroscience
King’s College London
London
SE5 8AF
United Kingdom
| Alice.Egerton@kcl.ac.uk |
Study information
| Study design | Interventional randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Scientific title | CLEAR: (CLozapine in EARly psychosis) A Multi-Centre, Randomised Controlled trial of Clozapine for Young People with Treatment Resistant Psychosis in Real World Settings |
| Study acronym | CLEAR |
| Study hypothesis | The primary objective is to compare the treatments on the change in total PANSS score from baseline to 12 weeks. The secondary objectives are to compare the treatments on function, side effects, quality of life, subjective improvement and cost-effectiveness. Added 01/02/2023: In addition, in an embedded mechanistic study we will test the hypothesis that, compared to other antipsychotics, treatment with clozapine is associated with a greater reduction in proinflammatory cytokines, brain glutamate and regional cerebral blood flow, and an increase in anti-inflammatory cytokines and glutathione. |
| Ethics approval(s) | Approved 12/12/2022, London - Dulwich Research Ethics Committee (Health Research Authority, Skipton House, 80 London Road, London, SE1 6LH, UK; +44 (0)2071048089; dulwich.rec@hra.nhs.uk), ref: 22/LO/0605 |
| Condition | Treatment-resistant psychosis |
| Intervention | Multi-centre, open label, blind-rated (primary outcome), 1:1 randomised controlled effectiveness trial of clozapine versus treatment as usual in children and young people (<25) with treatment resistant schizophrenia. Intervention: Clozapine, oral, flexible dose within dose range defined by British National Formulary (BNF); (Maximum dose = 900 mg per day), at the discretion of the prescriber, for 12 weeks. Following this, if clozapine is continued, it will no longer be classified as an investigational medicinal product. Control: Any oral antipsychotic in TAU group ATC code – N05A (other than clozapine ATC code – N05AH02 and Lithium – N05AN), within licensed dose range defined by BNF, for 12 weeks. The choice of antipsychotic will be agreed by the clinical team in collaboration with the participant, and the dose titrated to achieve the best balance between response and adverse effects. Participants in both arms will be followed up at week 2, week 6 and week 12. Following this it will be a clinical decision as to whether the participant continues on the same medication, or switches to a different one and they will be followed-up for 12 months through clinical notes and, whenever possible, videolink assessments (week 24 and 52). This trial is a single-blind, randomised, controlled trial. The raters will be centralised and blinded to minimise observer bias. A web based randomisation system will be designed, using the bespoke KCTU randomisation system. The randomisation system will be created in collaboration with the trial analyst/s and the CI and maintained by the King’s Clinical Trials Unit for the duration of the project. It will be hosted on a dedicated server within KCL. (added 01/02/2023) Additionally, in an embedded mechanistic study, brain Magnetic Resonance Imaging (MRI) scans and blood samples will be acquired at baseline and 12 weeks in a subset of participants. The MRI session will include acquisition of structural images, proton magnetic resonance spectroscopy (1H-MRS) to measure levels of glutamate, GSH and other brain metabolites and arterial spin labelling to measure regional cerebral blood flow. The blood samples will be used to measure levels of pro- and anti-inflammatory cytokines and GSH. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Clozapine |
| Primary outcome measure | Change in total PANSS score from baseline to 12 weeks. |
| Secondary outcome measures | Assessment will take place at weeks 6, 12, 24 and 52: 1. Change in overall clinical impression (CGI) 2. Clinician rated level of adherence (CRS) 3. Side effects (GASS-C) 4. Quality of life (EQ-5D-Y) 5. Subjective experience (DAI-10) 6. Psychotropic treatment, service use and readmission rate, (EI-AD-SUS) 7. Change in PANSS sub-scale (positive, negative and general), and weight gain. (added 01/02/2023) In the embedded mechanistic study, outcomes will include, from baseline to 12 weeks: 1. Change in brain glutamate, measured using proton magnetic resonance spectroscopy (1H-MRS) 2. Change in brain glutathione, measured using 1H-MRS 3. Change in regional cerebral blood flow, measured using arterial spin labelling 4. Change in peripheral levels of glutathione and cytokines. |
| Overall study start date | 02/08/2022 |
| Overall study end date | 28/02/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 12 Years |
| Upper age limit | 25 Years |
| Sex | Both |
| Target number of participants | 260 |
| Participant inclusion criteria | Current inclusion criteria as of 24/04/2025: 1. Age ≥12 and <25 years at randomisation 2. Meets criteria for schizophrenia or related disorder, in the range ICD-10v2016 F20.x, F22.x-F29.x 3. Meets NICE criteria for treatment resistance, defined as: 3.1. Previous trials of at least two different antipsychotic drugs with adequate adherence (estimated <20% missed doses) – both treatment trials to exceed 4 weeks at adequate doses (within the dose range given in the British National Formulary and the British National Formulary for children) 3.2. At least 1 of these trials must be with a second-generation drug 4. Positive and Negative Syndrome Scale (PANSS) total ≥70, at least 2 items >4 5. Clinician Rating Scale [24] (CRS) >3 6. English or Welsh language sufficient to participate 7. Capacity to give informed consent OR has a legal representative able to give consent to the trial _____ Previous inclusion criteria as of 13/03/2024: 1. Age ≥12 and <25 years at randomisation 2. Meets criteria for schizophrenia or related disorder, in the range ICD-10v2016 F20.x, F22.x-F29.x 3. Meets NICE criteria for treatment resistance, defined as: 3.1. Previous trials of at least two different antipsychotic drugs with adequate adherence (estimated <20% missed doses) – both treatment trials to exceed 6 weeks at therapeutic dose (≥600 mg chlorpromazine equivalent). 3.2. At least 1 of these trials must be with a second-generation drug. 3.3. Failure to respond to NICE-recommended psychological treatment OR failure to engage in same. 4. Positive and Negative Syndrome Scale (PANSS) total ≥70, at least 2 items >4 5. Clinician Rating Scale [24] (CRS) >3. 6. English or Welsh language sufficient to participate. 7. Capacity to give informed consent OR has a legal representative able to give consent to the trial. _____ Previous inclusion criteria: 1. Age ≥12 and <25 years at randomisation 2. Meets criteria for schizophrenia or related disorder, in the range ICD-10v2016 F20.x, F22.x-F29.x 3. Meets NICE criteria for treatment resistance, defined as: 3.1. Previous trials of at least two different antipsychotic drugs with adequate adherence (estimated <20% missed doses) – both treatment trials to exceed 6 weeks at therapeutic dose (≥600 mg chlorpromazine equivalent). 3.2. At least 1 of these trials must be with a second-generation drug 3.3. Failure to respond to NICE-recommended psychological treatment OR failure to engage in same 4. Positive and Negative Syndrome Scale (PANSS) total ≥70, at least 2 items >4 5. Compliance Rating Scale [23] (CRS) >3 6. English or Welsh language sufficient to participate 7. Capacity to give informed consent OR has a consultee (normally a family member) able to give consent to the trial. |
| Participant exclusion criteria | Current exclusion criteria as of 13/03/2024: 1. Psychosis predominantly caused by substance misuse. 2. Pregnancy. 3. Breastfeeding. 4 Women of child-bearing potential (WOCBP*) not using at least acceptable methods of contraception** during the trial 5. Contra-indications to clozapine as listed in SmPC as follows: 5.1. Hypersensitivity to the active substance or to any of the excipients, listed in section 6.1. 5.2. Patients unable to undergo regular blood tests. 5.3. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). 5.4. History of clozapine-induced agranulocytosis. 5.5. Impaired bone marrow function. 5.6. Uncontrolled epilepsy. 5.7. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions. 5.8. Circulatory collapse and/or CNS depression of any cause. 5.9. Severe renal or cardiac disorders (e.g. myocarditis). 5.10. Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure. 5.11. Paralytic ileus. 5.12. Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged. 6. Previous adequate trial of clozapine. 7. CNS disorders (ICD-10 G00-26; G40-41, G45-46; G80-94, G97). 8. Concurrent medications with documented interactions with antipsychotics. 9. Participation in a clinical trial involving any investigational medical product (licensed or unlicensed) within the last 3 months. 10. Positive test for COVID-19 within the past 10 days. 11. For participation in the substudy MRI scan only, standard contraindications to MRI at 3 Tesla such as ferromagnetic or electronic implants. * WOCBP defined as: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. ** acceptable methods of contraception include: • progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action • male or female condom with or without spermicide *** • cap, diaphragm or sponge with spermicide *** *** A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods Acceptable methods are the minimum requirement. It should be noted that the requirement for ‘at least acceptable methods of contraception’ would include the above methods but also include all ‘highly effective’ methods listed below: 1. Combined (estrogen and progestogen containing) hormonal 2. Contraception associated with inhibition of ovulation 1: 2.1. Oral 2.2. Intravaginal 2.3. Transdermal 3. Progestogen-only hormonal contraception associated with inhibition of ovulation 1: 3.1. Oral 3.2. Injectable 3.3. Implantable 4. Intrauterine device (IUD) 5. Intrauterine hormone-releasing system ( IUS) 6. Bilateral tubal occlusion 7. Vasectomised partner 8. Sexual abstinence (if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments). Previous exclusion criteria: 1. Psychosis predominantly caused by substance misuse 2. Pregnancy 3. Breastfeeding 4. Contra-indications to clozapine as listed in BNF SmPC as follows: 4.1. Hypersensitivity to the active substance or to any of the excipients 4.2. Patients unable to undergo regular blood tests. 4.3. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). 4.4. History of clozapine-induced agranulocytosis. 4.5. Impaired bone marrow function. 4.6. Uncontrolled epilepsy. 4.7. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions. 4.8. Circulatory collapse and/or CNS depression of any cause. 4.9. Severe renal or cardiac disorders (e.g. myocarditis). 4.10. Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure. 4.11. Paralytic ileus. 4.12. Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged. 5. Previous adequate trial of clozapine 6. CNS disorders (ICD-10 G00-26; G40-41, G45-46; G80-94, G97). 7. Concurrent medications with documented interactions with antipsychotics 8. Participation in a medicinal trial involving an unlicensed, investigational medical product within the last 3 months 9. Positive test for COVID-19 within the past 10 days. |
| Recruitment start date | 24/11/2023 |
| Recruitment end date | 31/08/2026 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Beckenham
BR3 3BX
United Kingdom
London
SE5 8AZ
United Kingdom
Dryden Road
Exeter
EX2 5AF
United Kingdom
Headington
Oxford
OX3 7JX
United Kingdom
Pendlebury
Swinton
Manchester
M27 4HA
United Kingdom
Wakefield
WF1 3SP
United Kingdom
Sponsor information
University/education
Institute of Psychiatry, Psychology and Neuroscience
16 De Crespigny Park
London
SE5 8AF
England
United Kingdom
| Phone | +44 20 7188 5732 |
|---|---|
| rebecca.newton@kcl.ac.uk | |
| Website | http://www.kcl.ac.uk/index.aspx |
"ROR" |
https://ror.org/0220mzb33 |
Hospital/treatment centre
Institute of Psychiatry, Psychology and Neuroscience
King's College London
16 De Crespigny Park
London
SE5 8AF
England
United Kingdom
| Phone | +44 20 7848 0339 |
|---|---|
| slam-ioppn.research@kcl.ac.uk | |
| Website | http://www.slam.nhs.uk/ |
|
"ROR" |
https://ror.org/015803449 |
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 | 28/02/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Peer reviewed scientific journals Conference presentation Submission to regulatory authorities Other All anonymised study data will be stored on a MACRO database. This will enable the sharing of data and future analysis. Participants are asked on the consent form that they understand information collected will be used to support other research in the future, and may be shared anonymously with other researchers in accordance with the terms of the NIHR funding for the study. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 14/02/2024 | 15/02/2024 | Yes | No | |
| Protocol file | version 4.0 | 01/08/2023 | 13/03/2024 | No | No |
| Protocol file | version 6.0 | 27/08/2024 | 24/04/2025 | No | No |
Additional files
Editorial Notes
24/04/2025: The following changes were made to the study record:
1. Uploaded protocol v6.0 (not peer-reviewed) as an additional file.
2. The inclusion and exclusion criteria were updated.
13/03/2024: The following changes were made to the study record:
1. Protocol uploaded.
2. The inclusion and exclusion criteria were updated.
12/03/2024: The recruitment start date was changed from 31/01/2023 to 24/11/2023. Study website and ethics approval added.
15/02/2024: Publication reference added.
01/02/2023: The following changes were made to the trial record to include mechanistic sub study:
1. A contact was added.
2. The interventions were updated.
3. The secondary outcome measures were updated.
4. The study hypothesis was updated
5. The plain English summary was updated to reflect these changes.
02/12/2022: Internal review.
29/11/2022: Internal review.
10/08/2022: Trial's existence confirmed by NHS HRA.
