A phase III randomized, double-blinded, placebo-controlled parallel group trial to examine the efficacy and safety of BI 425809 once daily over 26 week treatment period in patients with schizophrenia

Study ID: 46133
Short Title: BI trial 1346-0011/-0012/-0013
Organisation: Southern Health NHS Foundation Trust
Location: Forest Lodge
Condition: Psychosis - schizophrenia
Main Specialty: Mental Health
Expected End Date: 06/10/2023
Postcode: SO40 2RZ
Contact Name: R&D department
Contact Email: research@southernhealth.nhs.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

1. Signed and dated written informed consent in accordance with ICH Harmonized Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial. 2. Male or female patients who are 18-50 years (inclusive) of age at time of consent. 3. Diagnosis of schizophrenia utilizing Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) with the following clinical features: • Outpatient, clinically stable and in the residual (non-acute) phase of their illness. • No hospitalization or increase in level of psychiatric care due to worsening of schizophrenia within 3 months prior to randomization. 4. Patients should have functional impairment in day-to-day activities such as difficulties following conversation or expressing themselves, difficulties to stay focused, difficulties to remember instructions, what to say or how to get to places, per investigator judgement. 5. Patients maintained on current antipsychotic treatment (minimum 1 and maximum 2 antipsychotics, but clozapine is not allowed) for at least 3 months and on current dose for at least 35 days prior to randomization. o Doses should be within the recommended dose range listed in the approved product labelling of the country where the trials are being conducted. o Switch from 1 month to 3 month injectable formulation of same antipsychotic during the 3 months prior to randomization is allowed, but not with in last 35 days prior to randomization. o If the total dose is stable, different dosage forms of the same antipsychotic treatment will be considered as one antipsychotic. 6. Patients with any other concomitant psychoactive medications (except for anticholinergics) need to be maintained on same drug for at least 3 months and on current dose/ regimen for at least 35 days prior to randomization. o Maximum daily benzodiazepine load of up to 1 mg lorazepam-equivalent and hypnotic load up to 0.25 mg brotizolam-equivalent as needed (pro re nata, prn). Table of relevant medications and their equivalencies will be provided in the ISF. o For any other psychoactive medications, doses should be within the recommended dose range listed in the approved product labelling of the country where the trials are being conducted. 7. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3 (R2)) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria will be provided in the clinical trial protocol. Such methods should be used throughout the trial, and for a period of at least 35 days after last trial drug intake, and the patient must agree to periodic pregnancy testing during participation in the trial. 8. Have a study partner, defined as any person who knows the patient well, has been capable of interacting with the patient on regular basis, preferably consistent throughout the study, either private or professional. o The study partner must interact with the subject minimum 1 hour per week and, preferably, at least 2 times a week. At least one interaction per week should be in person. o The study partner must have educational achievement of minimum 8th grade o Professional study partner (e.g. study nurse, social worker etc.) are allowed if not involved in any of the protocol assessments. 9. Patients must exhibit reliability and physiologic capability (e.g. sufficient hearing, vision etc.), to comply with all protocol procedures, in the investigator’s opinion and educational achievement of minimum 8th grade. 10. Patients and his/ her study partner must be fluent in the language of the batteries/ questionnaires.

1. Participant with current DSM5 diagnosis other than Schizophrenia, including but not limited to bipolar, schizoaffective, major depressive disorder etc. M.I.N.I. for Psychotic disorders should be used for guidance. 2. Cognitive impairment due to developmental (e.g. Asperger’s disorder), neurological (e.g., epilepsy, stroke) or other disorder including head trauma, or patients with dementia. 3. Severe movement disorders o Leading to cognitive impairment (e.g. Parkinson dementia), or o Interfering with the efficacy assessments, or o Due to antipsychotic treatment that cannot be controlled with low dose anticholinergic treatment (equal to maximum 1 mg benztropin twice daily). Table with relevant medications and their equivalencies will be provided in the ISF. 4. Any suicidal behaviour in the past 1-year prior to screening and during the screening period. 5. Suicidal ideation of type 5 in the C-SSRS in the past 3 months (i.e. active suicidal thought with plan and intent) prior to screening and up to and including Visit 2. • Patients with Suicidal Ideation type 4 in the C-SSRS in the past 3 months (active suicidal thought with intent but without specific plan), can be randomized in the study, if assessed and documented by a licensed mental health professional that there is no immediate risk of suicide. 6. History of moderate or severe substance use disorder (other than caffeine and nicotine), as defined in DSM-5 within the last 12 months prior to informed consent. 7. Positive urine drug screen at Visit 1 based on central lab test. (Drugs to be tested: Cannabis, Barbiturates, Opiates, Cocaine, Amphetamines, Methadone, PCP) Patients testing positive for cannabis or opioids at Visit 1 may be re-tested once (consider long half-life of cannabis) during the screening period, if there is expectation that the patient is not a regular user, and at the discretion of the investigator. 8. Patients who were treated with any of the following within the last 6 months prior to randomization: o Clozapine o Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil) o Ketamine infusion o Electroconvulsive therapy (ECT). 9. Participation in any investigational psychoactive drug trial (both industry/ academic) in last 6 months, and 30 days or 5 half-lives for no-psychoactive drugs, prior to randomization. 10. Previous participation in any BI 425809 trial. 11. Patients who are treated with any of the following within the last 35 days prior to randomization: • Strong or moderate CYP3A4 inhibitors including grape fruit juice* • Strong or moderate CYP3A4 inducers including St. John’s wort (Hypericum perforatum)* *List of relevant medication will be provided as a part of ISF. • Dietary supplements and herbal remedies that may impact cognition, in the investigator´s judgement • Medication with negative impact on cognition such as antiepileptics, topiramate or any other drug that may potentially counteract the pro-cognitive effects of BI 425809. • Tricyclic antidepressants • Traditional Chinese medicine/ non-Western therapy • Medical devices therapy (e.g. TMS, neurofeedback) 12. Patients who plan to change their current habits of alcohol, nicotine or caffeine use, or on diet etc., during the treatment period. 13. Patients who have participated in a clinical trial with repeated assessments (i.e. a single assessment is not exclusionary) with the MATRICS Consensus Cognitive Battery (MCCB) and/ or any other schizophrenia cognitive battery within 3 months prior to screening. 14. Any formal Cognitive Remediation Therapy (CRT) within 3 months prior to screening. Initiation of CRT is not allowed during the trial. 15. Initiation or change in any type or frequency of psychotherapy (e.g. cognitive behavioural therapy (CBT), social skills training, vocational therapy) within the last 3 months prior to randomization. Patients with ongoing, stable psychotherapy > 3 months prior to randomization (and intend to maintain the same frequency during the trial) may qualify as per clinical judgement of the investigator. 16. Any of the following, in the judgment of the investigator: • Clinically significant finding of the physical examination, vital signs (including blood pressure (BP) and pulse rate (PR)), ECG or laboratory value (as measured by the central laboratory) that would jeopardize the patient´s safety while participating in the trial or their capability to participate in the trial. • Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease or any other clinical condition that would jeopardize the patient´s safety while participating in the trial or capability to participate in the trial. • Significant or unstable physical condition that may require change in medication or hospitalization that would impact cognitive function. • Planned major surgery requiring withdrawal from study medication for more than 2 weeks during the study period. Note: Please contact sponsor in case of you have question. 17. Haemoglobin (Hb) less than 120 g/L (12g/dL) in men or 115 g/L (11.5g/dL) in women at Visit 1 as assessed by the central lab report. Patients with low Hb at screening can be re-screened once the cause of low Hb was successfully treated. The reason and its treatment must be documented in the source documents. 18. History of any hemoglobinopathy (for example thalassemia or sickle-cell anemia). 19. Severe renal impairment defined as an eGFR < 30mL/min/1.73m² in the Visit 1 central lab report. 20. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 times upper limit of normal as determined in the Visit 1 central lab report. 21. Known history of HIV and/ or known on-going Hepatitis B or C infections. 22. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix. 23. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 24. Patient who did not make an effortful attempt to complete the cognition battery at Visit 1 in the clinical judgement of the investigator. 25. Patients with an allergy to BI 425809 and/or any of the excipients (including lactose). A list of BI 425809 and placebo ingredients will be provided in the ISF.

This study is open to adults with schizophrenia. Schizophrenia can affect the way a person thinks, their memory and their mental functioning. Examples include struggling to remember things, or to read a book or pay attention to a movie. Some people have difficulty calculating the right change or planning a trip so that they arrive on time. The purpose of this study is to find out whether a medicine called BI 425809 improves learning and memory in people with schizophrenia. Participants are put into two groups randomly, which means by chance. One group takes BI 425809 tablets and the other group takes placebo tablets. Placebo tablets look like BI 425809 tablets but do not contain any medicine. Participants take a tablet once a day for 26 weeks. In addition, all participants take their normal medication for schizophrenia. During this time, doctors regularly test learning and memory of the participants by use of questionnaires, interviews, and computer tests. The results of the mental ability tests are compared between the groups. Participants are in the study for about 8 months and visit the study site about 14 times. During this time, doctors regularly check participants' health and take note of any unwanted effects

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