A Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label, Long-Term Safety Phase to Evaluate the Efficacy and Safety of TV-44749 in Adults With Schizophrenia

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of TV-44749 in adult patients with schizophrenia. A key secondary objective is to further evaluate the efficacy of TV-44749 based on additional parameters in adult patients with schizophrenia. A secondary objective is to evaluate the safety and tolerability of TV-44749 in adult patients with schizophrenia Another secondary objective of this study is to evaluate the efficacy of TV-44749 from baseline to endpoint in Period 1 in adult patients with schizophrenia. Total study duration is up to 61 weeks, and treatment duration is up to 56 weeks, with weekly visits during the first 8 weeks and then monthly in-clinic visits with weekly calls during the remainder of the treatment period.

Detailed Description
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Patients with exacerbation of schizophrenia may be included. The study will be composed of 2 periods: Period 1 (the double-blind, placebo-controlled, efficacy and safety period) and Period 2 (open-label long term safety period). For each patient, the duration of Period 1 will be 8 weeks, and the duration of Period 2 will be up to 48 weeks. In Period 1, patients will be randomized to one of 3 TV-44749 treatment groups or a placebo group in a 1:1:1:1 ratio. All patients will be randomized again to one of the TV44749 treatment groups in a 1:1:1 ratio for Period 2. The end-of-treatment and follow-up visits will be at 4 and 8 weeks after the last dose of investigational medicinal product administration, respectively.

Official Title
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A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study With an Open-Label, Long-Term Safety Phase to Evaluate the Efficacy, Safety, and Tolerability of Olanzapine for Extended-Release Injectable Suspension (TV-44749) for Subcutaneous Use as Treatment of Adult Patients With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: TV-44749 - Dose level 1
* Drug: TV-44749 - Dose level 2
* Drug: TV-44749 - Dose level 3
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has a current confirmed diagnosis of schizophrenia according to the DSM-5, for >1 year The participant has exacerbation of schizophrenia that started ≤8 weeks prior to screening and would benefit from psychiatric hospitalization or continued hospitalization for symptoms of schizophrenia. Participants who have received an antipsychotic treatment (other than clozapine) in the past year must have been responsive based on the investigator's judgment (and based on discussions with family members, caregivers, or healthcare professionals, as applicable). Body mass index between 18.0 and 40.0 kg/m2, inclusive, at the time of screening Women may be included only if they have a negative beta-human chorionic gonadotropin (β-HCG) test at screening and baseline Women of childbearing potential must agree not to try to become pregnant, and, unless they have exclusively same-sex partners, must agree to use a highly effective method of contraception prior to the first administration of IMP, and agree to continue the use of this method for the duration of the study, and for 70 days after the last dose of IMP The participant is in adequate health as determined by medical and psychiatric history, medical examination, electrocardiogram (ECG), serum chemistry, hematology, coagulation urinalysis, and serology. NOTE- Additional criteria apply, please contact the investigator for more information Exclusion Criteria: The participant has a current clinically significant DSM-5 diagnosis other than schizophrenia (has a primary current diagnosis other than schizophrenia or a comorbid diagnosis that is primarily responsible for the current symptoms and functional impairment). The participant has a known history of the following: (a) borderline personality disorder, antisocial personality disorder, or bipolar disorder; (b) traumatic brain injury causing ongoing cognitive difficulties, Alzheimer's disease, or another form of dementia, or any chronic organic disease of the central nervous system; and (c) intellectual disability of a severity that would impact ability to participate in the study. The participant was hospitalized for >14 days (with the exception of social or administrative hospitalization) in the current exacerbation episode prior to screening. The participant has a significant risk of violent behavior based on the participant's medical history or investigator's judgment. The participant has a significant risk of committing suicide based on the participant's medical history or C-SSRS, and the investigator's judgment. The participant is currently using an LAI antipsychotic or is still under the coverage period of the specific LAI at time of screening. The participant has taken clozapine or has received electroconvulsive therapy within the last 12 months prior to screening. The participant is currently receiving daily oral olanzapine at a dose >20 mg/day. The participant has current or a history of known hypersensitivity to olanzapine or any of the excipients of TV-44749 or the oral formulation of olanzapine. The participant has had a significant sedation or delirium after antipsychotic treatment according to medical and psychiatric history and as judged by the investigator or suffered from delirium due to a medical condition. The participant has a non-fasting glucose level of ≥200 mg/dL at screening The participant meets criteria for moderate to severe substance use disorder (based on DSM-5 criteria) within the past 6 months (excluding those related to caffeine or nicotine) NOTE- Additional criteria apply, please contact the investigator for more information

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TV-44749 - Dose level 1<br>Low dose regimen | Drug: TV-44749 - Dose level 1<br>* In Period 1, 2 monthly injections. In Period 2, up to 12 monthly injections<br>|
| Experimental: TV-44749 - Dose level 2<br>Medium dose regimen | Drug: TV-44749 - Dose level 2<br>* In Period 1, 2 monthly injections, In Period 2 up to 12 monthly injections<br>|
| Experimental: TV-44749 - Dose level 3<br>High dose regimen | Drug: TV-44749 - Dose level 3<br>* In Period 1, 2 monthly injections. In Period 2, up to 12 monthly injections<br>|
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br>* In Period 1, 2 monthly injections (Period 1 only)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to week 8 in the Positive and Negative Syndrome Scale (PANSS) total score | Data gathered from this assessment procedure are applied to the PANSS ratings. Each of the 30 items is accompanied by a specific definition as well as detailed anchoring criteria for all seven rating points. These seven points represent increasing levels of psychopathology, as follows: 1- absent 2- minimal 3- mild 4- moderate 5- moderate severe 6- severe 7- extreme. | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Global Impression-Severity (CGI-S) scale score from baseline to week 8 | The CGI-S rates this severity of a 1-7 scale, with (1) representing normal symptoms, meaning the patient is not ill. The highest on the scale, (7), represents patients among the most severely ill. Right in the middle at (4), a patient will be defined as moderately ill. | Baseline, Week 8 | 
| Change in Personal and Social Performance Scale (PSP) score from baseline to week 8 | The PSP is a clinician-based rating instrument providing an overall rating of personal and social functioning in psychiatric patients on a scale of 0 (grossly impaired functioning) to 100 (excellent functioning). | Baseline, Week 8 | 
| Number of participants reporting at least one Adverse Event | Adverse events (including serious adverse events, extrapyramidal symptoms, injection pain and other injection site reactions), vital signs (blood pressure, pulse and orthostatic changes, and temperature), body weight, lab tests and ECGs. | Baseline to Week 8 | 
| Number of participants reporting at least one Adverse Event | Adverse events (including serious adverse events, extrapyramidal symptoms, injection pain and other injection site reactions), vital signs (blood pressure, pulse and orthostatic changes, and temperature), body weight, lab tests and ECGs. | Week 8 to Week 60 | 
| Change in total PANSS score from baseline to weeks 1, 2, and 4 |  | Baseline, Week 1, Week 2, Week 4 | 
| Change in Clinical Global Impression-Improvement (CGI-I) scale score from baseline to weeks 4 and 8 | CGI-I scores range from 1 to 7: 0=not assessed (missing), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. | Baseline, Week 4, Week 8 | 
| Change in CGI-S scale score from baseline to weeks 1, 2, and 4 |  | Baseline, Week 1, Week 2, Week 4 | 
| Change in Patient Global Impression-Improvement (PGI-I) scale score from baseline to week 8 | The PGI-I score ranges from 1 (Very much better) through to 7 (Very much worse). The lower the score, the better the improvement. | Baseline, Week 8 | 
| Change in PGI-I scale score from baseline to weeks 2 and 4 |  | Baseline, Week 2, Week 4 | 
| Change in Schizophrenia Quality of Life Scale (SQLS) score from baseline to weeks 4 and 8 | The SQLS questionnaire assesses schizophrenia quality of life. A higher score indicates worse quality of life. | Baseline, Week 4, Week 8 | 
| Change in PSP score from baseline to week 4 |  | Baseline, Week 4 | 
| Number of participants reporting use of at least one Concomitant Medication |  | Baseline to Week 8 | 
| Number of participants reporting use of at least one Concomitant Medication |  | Week 8 to Week 60 | 
| Number of participants that discontinued the trial |  | Baseline to Week 8 | 
| Number of participants that discontinued the trial |  | Week 8 to Week 60 | 
| Number of participants who Discontinued the trial due to Adverse Events |  | Baseline to Week 8 | 
| Number of participants who Discontinued the trial due to Adverse Events |  | Week 8 to Week 60 | 
| Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) total score |  | Baseline to Week 8 | 
| Change from Baseline in total score in Abnormal Involuntary Movement Scale (AIMS) |  | Week 8 to Week 60 | 
| Change from baseline in Simpson-Angus Scale (SAS) mean score |  | Baseline to Week 8 | 
| Change from baseline in Simpson-Angus Scale (SAS) mean score |  | Week 8 to Week 60 | 
| Change from baseline in Barnes Akathisia Rating Scale (BARS) total score |  | Baseline to Week 8 | 
| Change from baseline in Barnes Akathisia Rating Scale (BARS) total score |  | Week 8 to Week 60 | 
| Number of participants with any suicidal ideation or suicidal behavior according to the Columbia Suicide Severity Rating Scale (C-SSRS) |  | Baseline to Week 8 | 
| Number of participants with any suicidal ideation or suicidal behavior according to the Columbia Suicide Severity Rating Scale (C-SSRS) |  | Week 8 to Week 60 | 
| Change from baseline in Calgary Depression Scale for Schizophrenia (CDSS) |  | Baseline to Week 8 | 
| Change from baseline in Calgary Depression Scale for Schizophrenia (CDSS) |  | Week 8 to Week 60 |