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

Participants 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 participant, the duration of Period 1 will be 8 weeks, and the duration of Period 2 will be up to 48 weeks. In Period 1, participants will be randomized to one of 3 TV-44749 treatment groups or a placebo group in a 1:1:1:1 ratio. All participants 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.

Primary Outcome Measures

1. Double-blind Period: Change in the Positive and Negative Syndrome Scale (PANSS) Total Score From Baseline to Week 8
   The PANSS is a 30-item scale used to evaluate positive and negative symptoms of schizophrenia. The PANSS was used to identify the presence and severity of psychopathology symptoms, the relationship of these symptoms to one another, and the global psychopathology. Each item was scored on a 7-point scale ranging from 1 (absent) to 7 (extreme). The positive symptom scale includes 7 items with a maximum score of 49; the negative symptom scale includes 7 items with a maximum score of 49; and the general psychopathology scale includes 16 items with a maximum score of 112. The total score was the sum of 30-item scale, ranging from 30 (absent) to 210 (extreme), with a higher score indicating greater severity of symptoms. Least square (LS) mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and PANSS total score at baseline as covariates.

Secondary Outcome Measures

1. Double-blind Period: Change in Clinical Global Impression-Severity (CGI-S) Scale Score From Baseline to Week 8
   The CGI-S is a 7-point scale that assess the participant's current severity of illness on a scale of 1 to 7, where 1=normal/not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill patients. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and CGI-S score at baseline as covariates.
2. Double-blind Period: Change in Personal and Social Performance Scale (PSP) Score From Baseline to Week 8
   The PSP is a clinician-rated instrument that measures personal and social functioning in participants with schizophrenia. The PSP is a 100-point single-item rating scale, divided into 10 equal intervals, where 0 (grossly impaired functioning) to 100 (excellent functioning). The score was based on the assessment of participant's functioning in 4 categories: 1) socially useful activities, including work and study; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviors. Higher scores represented better personal and social functioning, with ratings from 91 to 100 indicating more than adequate functioning, while scores under 30 indicating poor functioning that required intensive supervision. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and PSP score at baseline as covariates.
3. Double-blind Period: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
   An AE was defined as any untoward medical occurrence in a participant who received the study drug without regard to possibility of causal relationship. The SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in the Reported AE section.
4. Integrated Study Period: Number of Participants With AEs and SAEs
   An AE was defined as any untoward medical occurrence in a participant who received the study drug without regard to possibility of causal relationship. The SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in the Reported AE section.
5. Double-blind Period: Change in PANSS Total Score From Baseline to Weeks 1, 2, and 4
   The PANSS is a 30-item scale used to evaluate positive and negative symptoms of schizophrenia. The PANSS was used to identify the presence and severity of psychopathology symptoms, the relationship of these symptoms to one another, and the global psychopathology. Each item was scored on a 7-point scale ranging from 1 (absent) to 7 (extreme). The positive symptom scale includes 7 items with a maximum score of 49; the negative symptom scale includes 7 items with a maximum score of 49; and the general psychopathology scale includes 16 items with a maximum score of 112. The total score was the sum of 30-item scale, ranging from 30 (absent) to 210 (extreme), with a higher score indicating greater severity of symptoms. Least square (LS) mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and PANSS total score at baseline as covariates.
6. Double-blind Period: Clinical Global Impression-Improvement (CGI-I) Scale Score at Weeks 4 and 8
   The CGI-I is a 7-point scale that permits a global evaluation of the participant's overall improvement in symptoms on a scale of 1 to 7, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and CGI-I score at baseline as covariates.
7. Double-blind Period: Change in CGI-S Scale Score From Baseline to Weeks 1, 2, and 4
   The CGI-S is a 7-point scale that assess the participant's current severity of illness on a scale of 1 to 7, where 1=normal/not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=among the most extremely ill patients. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and CGI-S score at baseline as covariates.
8. Double-blind Period: Patient Global Impression-Improvement (PGI-I) Scale Score at Weeks 2, 4, and 8
   The PGI-I scale is a 1-item participant-rated instrument that measures improvement of the participant's disease. The participant rated the perceived change in his/her condition in response to therapy on a scale of 1 to 7, where 1=very much better, 2=much better, 3=a little better, 4=no change, 5=a little worse, 6=much worse, 7=very much worse. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and PGI-I score at baseline as covariates.
9. Double-blind Period: Change in Schizophrenia Quality of Life Scale (SQLS) Total Score From Baseline to Weeks 4 and 8
   The SQLS Revision 4 was administered to capture quality of life. The 33-item measure yields subscales pertaining to psychosocial (20 items) and cognition/vitality factors (13 items). Each item was scored on a 5-point scale (1 - never, 2 - rarely, 3 - sometimes, 4 - often, 5 - always). Individual domain and total scores were standardized by scoring algorithm from 0 (best health status) to 100 (worst health status) scale, with higher scores indicating comparatively lower quality of life.
10. Double-blind Period: Change in PSP Score From Baseline to Week 4
    The PSP is a clinician-rated instrument that measures personal and social functioning in participants with schizophrenia. The PSP is a 100-point single-item rating scale, divided into 10 equal intervals, where 0 (grossly impaired functioning) to 100 (excellent functioning). The score was based on the assessment of participant's functioning in 4 categories: 1) socially useful activities, including work and study; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviors. Higher scores represented better personal and social functioning, with ratings from 91 to 100 indicating more than adequate functioning, while scores under 30 indicating functioning so poor that intensive supervision was required. LS mean was calculated using a repeated measures model with treatment, study visit, treatment visit interaction, stratification variables (sex and geographic region), age, and PSP score at baseline as covariates.
11. Double-blind Period: Number of Participants Receiving At Least 1 Concomitant Medication
    Concomitant medications included all medications taken while the participant was treated with the study drug. Any concomitant medication received by the participant for AEs was recorded on the case report form (CRF). Concomitant medications included: zolpidem, zopiclone, zaleplon, or diphenhydramine for insomnia; benztropine, trihexyphenidyl, or diphenhydramine for parkinsonian symptoms; propranolol and benzodiazepines for akathisia; lorazepam on an as-needed basis for indications other than akathisia (for example, anxiety); and antihistamine and anticholinergic drugs for agitation and insomnia.
12. Integrated Study Period: Number of Participants Receiving At Least 1 Concomitant Medication
    Concomitant medications included all medications taken while the participant was treated with the study drug. Any concomitant medication received by the participant for AEs was recorded on the CRF. Concomitant medications included: zolpidem, zopiclone, zaleplon, or diphenhydramine for insomnia; benztropine, trihexyphenidyl, or diphenhydramine for parkinsonian symptoms; propranolol and benzodiazepines for akathisia; lorazepam on an as-needed basis for indications other than akathisia (for example, anxiety); and antihistamine and anticholinergic drugs for agitation and insomnia.
13. Double-blind Period: Change From Baseline to Week 8 in Abnormal Involuntary Movement Scale (AIMS) Total Score
    The AIMS is a 14-item scale that includes assessments of orofacial movements, extremity and truncal dyskinesia, examiner's judgment of global severity, subjective measures of awareness of movements and distress, and a yes/no assessment of problems concerning teeth and/or dentures. AIMS total score was calculated as a sum of items 1 through 7. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated from 0 (none) to 4 (severe) The AIMS total score for Items 1-7 ranged from 0 (no dyskinesia) to 28 (severe dyskinesia) with a higher score indicating greater severity of the condition.
14. Integrated Study Period: Change From Baseline to Week 60 in AIMS Total Score
    The AIMS is a 14-item scale that includes assessments of orofacial movements, extremity and truncal dyskinesia, examiner's judgment of global severity, subjective measures of awareness of movements and distress, and a yes/no assessment of problems concerning teeth and/or dentures. AIMS total score was calculated as a sum of items 1 through 7. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated from 0 (none) to 4 (severe) The AIMS total score for Items 1-7 ranged from 0 (no dyskinesia) to 28 (severe dyskinesia) with a higher score indicating greater severity of the condition.
15. Double-blind Period: Change From Baseline to Week 8 in Simpson-Angus Scale (SAS) Mean Score
    The SAS is a 10-item instrument for the assessment of neuroleptic-induced parkinsonism. The items on the scale include measurements of hypokinesia, rigidity, glabellar reflex, tremor, and salivation. Each item was rated on a 5-point scale (0 \[normal\] to 4 \[severe\]). The mean score was calculated by adding the individual item scores and dividing by 10, ranging from 0 (normal) to 4 (severe) with a higher score indicating greater severity of symptoms.
16. Integrated Study Period: Change From Baseline to Week 60 in SAS Mean Score
    The SAS is a 10-item instrument for the assessment of neuroleptic-induced parkinsonism. The items on the scale include measurements of hypokinesia, rigidity, glabellar reflex, tremor, and salivation. Each item was rated on a 5-point scale (0 \[normal\] to 4 \[severe\]). The mean score was calculated by adding the individual item scores and dividing by 10, ranging from 0 (normal) to 4 (severe) with a higher score indicating greater severity of symptoms.
17. Double-blind Period: Change From Baseline to Week 8 in Barnes Akathisia Rating Scale (BARS) Total Score
    The BARS is an instrument that assesses the severity of drug-induced akathisia. The BARS included 3 items for rating objective restless movements, subjective restlessness, and any subjective distress associated with akathisia that were scored on a 4-point scale of 0 (normal) to 3 (most severe) and summed up yielding a total score ranging from 0 (normal) to 9 (most severe). Higher scores indicated greater severity of akathisia.
18. Integrated Study Period: Change From Baseline to Week 60 in BARS Total Score
    The BARS is an instrument that assesses the severity of drug-induced akathisia. The BARS included 3 items for rating objective restless movements, subjective restlessness, and any subjective distress associated with akathisia that were scored on a 4-point scale of 0 (normal) to 3 (most severe) and summed up yielding a total score ranging from 0 (normal) to 9 (most severe). Higher scores indicated greater severity of akathisia.
19. Double-blind Period: Number of Participants With Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS)
    The C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.
20. Integrated Study Period: Number of Participants With Any Suicidal Ideation or Suicidal Behavior According to the C-SSRS
    The C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.
21. Double-blind Period: Change From Baseline to Week 8 in Calgary Depression Scale for Schizophrenia (CDSS) Score
    The CDSS is specifically designed to assess the level of depression separate from the positive, negative, and extrapyramidal symptoms in schizophrenia. This clinician-administered instrument consisted of 9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe) that are added together to form the CDSS depression total score for the participant ranging from 0 (absent) to 27 (severe) with higher scores indicating a higher severity of depression.
22. Integrated Study Period: Change From Baseline to Week 60 in CDSS Score
    The CDSS is specifically designed to assess the level of depression separate from the positive, negative, and extrapyramidal symptoms in schizophrenia. This clinician-administered instrument consisted of 9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe) that are added together to form the CDSS depression total score for the participant ranging from 0 (absent) to 27 (severe) with higher scores indicating a higher severity of depression.