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
Funder: Department of Health and Social Care

Abstract: Schizophrenia causes symptoms like “delusions” (being sure of something when nobody else can see any reason to believe it), “hallucinations” (most often, hearing voices when no one else can), “negative symptoms” (having reduced motivation or emotion) and muddled speech and thinking. The main treatment for it is “antipsychotic” medication. Schizophrenia usually starts in the twenties but it can begin during childhood or adolescence, when it is often more severe, causing many problems for the person and their family. If not treated, symptoms typically carry on for many years, so it is vital to get effective treatment as soon as possible._x000D_ Research shows that one antipsychotic, clozapine, works better than any other antipsychotics, and that clozapine has the best chance of working if people start it 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 for 25 and over who had already taken several other antipsychotic medications over the years. _x000D_ _x000D_ Because the illness so often starts in the teens or early twenties, we need to get a better understanding of what could help younger people. Research on antipsychotics in young people and children shows that antipsychotics do help children and young people with schizophrenia and similar illnesses, but there is little research focussed on clozapine in young people. Three well designed studies suggest that clozapine works better than other antipsychotics in children and young people, but the studies were too small to be conclusive. This means using clozapine for children is not based on strong evidence and doctors worry about side effects. This is why they still do not use clozapine often for children and young people. This means that some children might suffer symptoms they could avoid and if it is used years later it might work less well._x000D_ _x000D_ For these reasons, we plan to study clozapine as a treatment for schizophrenia and similar illnesses in young people. We will recruit only people under twenty five years old. We will recruit as many as possible aged under eighteen, from Child and Adolescent Mental Health Services. Recruiting just under-eighteens is not practical because these illnesses are rare in children and we plan to include 260 people in this study. All of them will still have delusions, hallucinations or muddled thinking after treatment with at least two antipsychotics. A computer will decide randomly whether each person will either take clozapine or another antipsychotic for twelve weeks. Participants who are allocated to take another antipsychotic will be allowed to take any antipsychotic other than clozapine. Researchers will then assess the young people’s symptoms. To stop them being biased the doctor doing the assessment will not know which drug the young person is taking. They will assess participants again several times over 12 weeks. At the end of the study we will see if clozapine reduced people’s symptoms more than other antipsychotics. We will also study people’s side effects, how well they feel life is going, how much their treatment costs the NHS and how often they need hospital treatment. After the main study is over we will contact the people again to see how they are doing in the longer term. The results will help us decide which treatment we should recommend so, it should help other people

Lay abstract: RESEARCH QUESTION: What is the clinical and cost-effectiveness and patient acceptability of clozapine for children and young people with treatment resistant schizophrenia in real-world settings?_x000D_ _x000D_ BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy. It is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotic drugs). In addition, it is the most effective of all antipsychotics in reducing hospital use, suicide, aggressive behaviour, violent crime, and substance misuse. However, it is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which patients require haematological monitoring. As treatment resistance is increasingly recognised earlier during the course of the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and both the NICE Guideline Development Group and James Lind Alliance have highlighted the lack of evidence about the efficacy and safety of clozapine in people under age 25. At present, most young patients with schizophrenia who meet criteria for treatment resistance are treated with standard antipsychotics, rather than the clozapine that is recommended by NICE. _x000D_ _x000D_ AIMS AND OBJECTIVES: The trial will assess whether clozapine is more effective than treatment as usual (TAU: standard antipsychotics), at the level of clinical symptoms, patient rated outcomes, quality of life and cost effectiveness. _x000D_ _x000D_ METHODS: This is a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (i.e. compared with other antipsychotics – clinician’s choice) for 12 weeks in 260 children and young people with TRS (<25 years old). We will recruit from NHS-funded secondary care, both inpatient and community settings, using a hub and spoke model, with 6 academic centres coordinating 30 recruitment sites. The primary outcome is the change in total blind-rated PANSS scores at 12 weeks from baseline. Secondary outcomes, include blind-rated clinical global impression, patient-rated outcomes, quality of life, adverse effects, treatment adherence and service use. Patients will be followed up for 12 months with the potential for further follow-up using clinical records. _x000D_ _x000D_ TIMELINES FOR DELIVERY: Preparations will begin on confirmation of funding, for a formal start date of 1/09/2021. Recruitment will run for 4.75 years from 1/03/2022 - 6/12/2026. The study will end on 28/02/2027. We will conduct an internal pilot, which will last for one year, starting at the point where 50% of sites are open, with strict go/no-go criteria. _x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: If, as hypothesised, clozapine is shown to be superior to standard antipsychotics, there will be a need to reshape services so that barriers to clozapine treatment in these populations, such as a lack of clozapine clinics in CAMHS services, are addressed. Whatever the results, this study will have important implications for NICE and other guideline producers, policymakers, academics, clinicians, service users and their families and the results will be disseminated to all these groups via the academic literature, continuing professional development, blogs and patient-facing educational materials delivered face to face, in print and online.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH