Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)

Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia

A Long-term, Phase 3, Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia

The purpose of this study is to assess the long-term safety, tolerability and efficacy of oral OPC-34712 as monotherapy in adults with schizophrenia.

Schizophrenia is a severely debilitating mental illness that affects approximately 1% of the world population. Hallucinations and delusions are the most striking characteristic positive symptoms of schizophrenia; however, more subtle negative symptoms (eg, social withdrawal and lack of emotion, energy, and motivation) may also be present. The first antipsychotics developed for the treatment of schizophrenia were effective against positive symptoms, but showed little efficacy for negative symptoms and were also associated with a high incidence of side effects. Second generation antipsychotics, represent a significant advancement in the treatment of psychotic disorders because they are effective and at the same time exhibit fewer side effects than first generation antipsychotics. Although generally safer than first generation antipsychotics, the second-generation antipsychotics are not devoid of undesirable side effects such as Hyperprolactinemia and weight gain. In addition, the safety of these drugs vary considerably.

A treatment-emergent adverse event (TEAE) is defined as an AE that started after start of investigational medicinal product (IMP) treatment; or if the event was continuous from baseline and was serious, IMP-related, or resulted in death, discontinuation, interruption or reduction of IMP.

The PANSS consisted of 3 subscales with 30 symptom constructs (positive subscale (7): delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/perseckion, and hostility; negative subscale (7): blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and conversation flow, stereotyped thinking and general psychopathology subscale (16): somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance). Severity was rated on 7-point scale with scores 1 (absence) & 7 (extremely severe). The PANSS total score was sum of rating scores for 7 positive, 7 negative, and 16 general psychopathology subscale items of PANSS panel.

The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In positive subscale, the 7 positive symptom constructs were: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility.

The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In negative subscale the severity was rated for the following 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking.

The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the investigator were to answer the following question: "Considering your total clinical experience with this particular population, how mentally ill was the participant at that time?" Response choices include: 0 = not assessed; 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 participants.

The PSP was a validated clinician-rated scale that measured personal and social functioning in four domains: socially useful activities (e.g, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment that determined the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.

The efficacy of study medication was rated for each participant using the CGI-I. The investigator rated the participant's total improvement whether or not it was due to the drug treatment. All responses were compared to the participant's condition at Screening/Baseline (i.e, Week 6 visit of Protocol NCT00905307). Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Response rate was defined as a reduction of ≥ 30% from Baseline in PANSS total score or CGI-I score of 1 (very much improved) or 2 (much improved) at the Last Visit.

The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).

Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score was the sum of the 8 components (delusions (P1), hallucinatory behavior (P3), grandiosity (P5), suspiciousness/persecution (P6), stereotyped thinking (N7), somatic concern (G1), unusual thought content (G9) and lack of judgment and insight (G12)) of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).

Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items (blunted affect (N1), emotional withdrawal (N2), poor rapport (N3), passive/apathetic social withdrawal (N4), lack of spontaneity and conversation flow (N6), motor retardation (G7) and active social avoidance (G16)) of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).

Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items (conceptual disorganization (P2), difficulty in abstract thinking (N5), mannerisms and posturing (G5), disorientation (G10), poor attention (G11), disturbance of volition (G13) and preoccupation (G15)) on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).

Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items (excitement (P4), hostility (P7), uncooperativeness (G8) and poor impulse control (G14)) on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).

Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items (anxiety (G2), guilt feelings (G3), tension (G4) and depression (G6)) on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).

Inclusion Criteria: Male or female subjects between 18 and 65 years of age, with a diagnosis of schizophrenia, as defined by DSM-IV-TR criteria Outpatient status at last visit of Trial 331-10-230 or Trial 331-10-231 Willing to discontinue all prohibitive psychotropic medications to meet protocol required washouts prior to and during the trial period. Other protocol specific inclusion criteria may apply. Exclusion Criteria: Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug Subjects with a current DSM-IV-TR Axis I diagnosis of: Schizoaffective disorder MDD Bipolar disorder Delirium, dementia, amnestic or other cognitive disorder Borderline, paranoid, histrionic, schizotypal, schizoid or antisocial personality disorder Subjects presenting with a first episode of schizophrenia Other protocol specific exclusion criteria may apply.

Correll CU, He Y, Therrien F, MacKenzie E, Meehan SR, Weiss C, Hefting N, Hobart M. Effects of Brexpiprazole on Functioning in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies. J Clin Psychiatry. 2022 Mar 1;83(2):20m13793. doi: 10.4088/JCP.20m13793.

Marder SR, Meehan SR, Weiss C, Chen D, Hobart M, Hefting N. Effects of Brexpiprazole Across Symptom Domains in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies. Schizophr Bull Open. 2021 May 1;2(1):sgab014. doi: 10.1093/schizbullopen/sgab014. eCollection 2021 Jan.

Newcomer JW, Eriksson H, Zhang P, Weiller E, Weiss C. Changes in metabolic parameters and body weight in brexpiprazole-treated patients with acute schizophrenia: pooled analyses of phase 3 clinical studies. Curr Med Res Opin. 2018 Dec;34(12):2197-2205. doi: 10.1080/03007995.2018.1498779. Epub 2018 Jul 27.

Forbes A, Hobart M, Ouyang J, Shi L, Pfister S, Hakala M. A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Maintenance Treatment in Adults with Schizophrenia. Int J Neuropsychopharmacol. 2018 May 1;21(5):433-441. doi: 10.1093/ijnp/pyy002.

Kane JM, Skuban A, Hobart M, Ouyang J, Weiller E, Weiss C, Correll CU. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016 Jul;174(1-3):93-98. doi: 10.1016/j.schres.2016.04.013. Epub 2016 May 14.