The INTENSIFY Trial: The Effect of a Six-Week Intensified Pharmacological Treatment (Third-Line Medication) for Schizophrenia Compared to Treatment as Usual (Second-Line Medication) in Participants Who Did Not Respond to a First-Line Medication Treatment.

This is a phase IV multicentre controlled, randomised open label trial for Schizophrenia Participants are randomised to either Treatment as usual (TAU) or Early Intensified Pharmacological Treatment (EIPT) Treatment as Usual (TAU): Switch to second line antipsychotic Early-Intensified Pharmacological Treatment (EIPT): Switch to clozapine If participants are randomised to the early-intensified pharmacological treatment (EIPT), there will be a switch to clozapine (investigational product). The clozapine initiation dosing regime, target dose, and safety monitoring regime will be according to SA Health clinical practice guidelines. Prescribing will be done by the study doctor(s) and dispensing of the product will be through the Lyell McEwin Hospital pharmacy. Participants in the EIPT group will receive Clozapine for a period of 6 weeks. The SA Health Clozapine Clinical Management Guidelines V2.0 dated 12/07/22 will be followed for prescription and management of clozapine. Initial dose: 12.5 mg orally once a day. Total daily dose increments of 25 mg to 50 mg to a target dose of 200 mg per day (administered in divided doses) by the end of week 2. From day 14 the dose can be increased in 50mg intervals every two to three days, depending on efficacy and side effects. Maximum dose is 900mg/day. For this study we are limited to a maximum of 600 mg/day by titration guidelines mandated by SA Health. The possibility of increased adverse reactions occurring at doses over 450 mg/day must be borne in mind. Clozapine prescribing and monitoring will be managed by the Principal Investigators/Psychiatrists and Sub Investigator/study doctor as per SA Health Clozapine Management Clinical Guideline Version 2.0 dated 12/07/22 (10) during the trial. This will include pre-commencement specific history taking, physical examination, blood tests, and outpatient echocardiogram outside of study time between screening and baseline visits. Participants will receive their clozapine treatment through the Lyell McEwin Pharmacy acting as treatment centre for the duration of the trial. They will be given a thermometer and instructed on how to take their temperature daily for the first 28 days of treatment, and to contact study staff immediately if they have a fever of greater than 38 degrees. The required weekly blood tests will be collected, processed and reported by their local pathology collection centre. The participants will be required to attend the Clinical Trials Unit weekly for medical review with a study doctor within 48 hours of blood testing each week that they are taking clozapine. This will be combined with study visits where possible to reduce the time burden on the participants. ECGs on weeks 1,2 and 4 of clozapine treatment will be completed and reported by their local collection centre. If EIPT-SZ participants wish to continue clozapine following completion of the trial and are not eligible for PBS-subsidy under Australian regulations, they can do so using a private (non-PBS) script issued by their treating clinician. If they wish to switch to a standard second-line antipsychotic (which will be fully subsidized by PBS), their prescribing physician will be advised by the study team to follow the switching instructions outlined in the clozapine PI, and to monitor their patient closely. Additionally, all EIPT-SZ patients will be seen at the LMH clinical trials unit by the study team weekly for another 4 weeks following conclusion of the 6-week trial. At all times during this period, they will be treated with a pharmacologically appropriate maintenance dose of an approved antipsychotic medication To ensure that the SZ TAU groups have an equal number of contact moments with the study team as the EIPT participants who are receiving treatment in the Clinical Trial unit once weekly these participants will be contacted by phone by the study team once a week (same timepoints as the EIPT medication administration). Similar questions on medication adherence and general wellbeing will be asked in the contact moments, either in person (EIPT group) or via a phone call (TAU group). These are expected to take 5 to 10 minutes. Throughout the study adherence and safety of treatment is measured by the comparison of side effects scale GASE - General Assessment of side Effects Questionnaires related to Medication Adherence, premature discontinuation timing and reason between treatment arms and the comparison use of concomitant medication between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of subjects represented by the trial subjects as well as the nature and extent of burden and risks All medications studied in the current trial are widely used (alone or in combination) in clinical practice and the risks for side effects are well established. In the current study, clinical practice is mimicked as much as possible to maximize generalizability and for feasibility purposes. Site visits and assessments are kept to a minimum to keep subject burden at an acceptable level, while meeting the objectives of the study. Blood samples are only collected when subjects provide consent; safety measures are performed as part of clinical routine. Overall, the risks are similar to daily clinical practice; the only difference relative to clinical practice is the application of early-intensified pharmacological treatment earlier in the illness. However, these intense treatment options are also commonly prescribed by clinicians. There are no indications in existing literature that the earlier introduction of these medications poses a safety risk.