Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia (ADVANCE)

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of adjunctive pimavanserin compared with adjunctive placebo in the treatment of the negative symptoms of schizophrenia

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Pimavanserin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, between 18 and 55 years of age A clinical diagnosis of schizophrenia with a minimum duration of 1 year Has predominant negative symptoms according to predefined study criteria The main background antipsychotic with which the subject is being treated must be one of the antipsychotics listed below: Aripiprazole Aripiprazole long-acting injectables: Abilify Maintena® Aristada® Risperidone Risperidone long-acting injection Olanzapine Lurasidone Cariprazine Brexpiprazole Asenapine Exclusion Criteria: Patient has a psychiatric disorder other than schizophrenia A urine drug screen (UDS) result at Baseline that indicates the presence of any tested prohibited substance of potential abuse, except marijuana a. Patients with a result indicating the presence of marijuana are permitted if they agree to abstain from marijuana use during the study and the medical monitor approves the subject's participation Patient has current evidence of a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies, which would affect the patient's ability to participate in the program Patient has had a myocardial infarction in the last six months Patient has a family or personal history or symptoms of long QT syndrome Patient has been hospitalized due to inadequate family support or care at the patient's primary residence, during the 8 weeks prior to screening Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all pre-specified entry criteria).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Pimavanserin<br>Drug- pimavanserin 34 mg, 20 mg, or 10 mg taken as two tablets + background antipsychotic, once daily by mouth | Drug: Pimavanserin<br>* Pimavanserin 34 mg, 20 mg, or 10 mg, taken as two tablets, once daily by mouth<br>|
| Placebo Comparator: Placebo<br>Placebo, taken as two tablets + background antipsychotic, once daily by mouth | Drug: Placebo<br>* Placebo, taken as two tablets, once daily by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) Total Score | The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia. | From baseline to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in the Personal and Social Performance Scale (PSP) Score | The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial functioning of subjects with schizophrenia. Ratings are based on 4 main areas i.e. (a) socially useful activities, including work and study; (2) personal and social relationships, (3) self-care; and (4) disturbing and aggressive behaviors. The time period assessed is past month. Higher scores denote better psychosocial functioning | From baseline to Week 26 | 
| Proportion of Negative Symptom Assessment-16 (NSA-16) Responders at Week 26 | The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia. NSA-16 responders were defined as patients with at least 20, 30, 50, or 75% percentage improvement in NSA-16 total score from baseline. | From baseline to Week 26 | 
| Change From Baseline to Week 26 in NSA-16 Global Negative Symptoms Rating | The global negative symptoms rating of the NSA-16 assesses overall severity on a 7-point scale from 1 to 7, with higher scores denoting more severe negative symptoms in schizophrenia. | From baseline to Week 26 | 
| Change From Baseline (CFB) to Week 26 in NSA-16 Domain Scores | The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 domain scores are the sum of item scores in each domain i.e. communication (min score 4, max score 24), emotion/affect (min 3, max 18), social involvement (min 3, max 18), motivation (min 4, max 24), and retardation (min 2, max 12); with higher scores denoting more severe negative symptoms in schizophrenia. | From baseline (BL) to Week 26 | 
| Change From Baseline to Week 26 in the Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH-S) of Negative Symptoms Score | The CGI-SCH-S is a clinician-rated, 7-point scale to evaluate positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the negative symptoms were evaluated. The score could range from 1 (normal, not ill) to 7 (among the most severely ill). | From baseline to Week 26 | 
| Clinical Global Impression of Schizophrenia Scale-Improvement (CGI-SCH-I) of Negative Symptoms Score at Week 26 | The CGI-SCH-I is a clinician-rated, 7-point scale to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The score could range from 1 (very much improved) to 7 (very much worse). | From baseline to Week 26 | 
| Proportion of CGI-SCH-I Responders (CGI-SCH-I Score of 1 or 2) at Week 26; Observed Cases | The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The 7-point scores range from 1 (very much improved) to 7 (very much worse); responders were defined as those with CGI-SCH-I of 1 or 2. The analysis includes observed cases; missing cases were not imputed. | From baseline to Week 26 | 
| Change From Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) Total Score | The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS total score is the sum of scores and ranges from a minimum of 30 to a maximum of 210. Higher scores denote more severe symptoms. | From baseline to Week 26 | 
| Change From Baseline (CFB) to Week 26 in PANSS Subscale Scores | The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS has 3 subscales that are the sums of the respective item scores, including the positive scale (min 7, max 49), negative scale (min 7, max 49), and general psychopathology scale (min 16, max 112). Higher scores denote more severe symptoms. | From baseline (BL) to Week 26 | 
| Change From Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score | The BACS is a performance-based assessment of treatment-related changes in cognition, assessing 6 domains of verbal memory and learning; working memory; motor function; verbal fluency; attention and speed of processing; and executive function. The 6 domains with their raw scores are: verbal memory 0-75; digit sequencing 0-28; token motor 0-100; verbal fluency 0-225; symbol coding 0-110; Tower of London 0-22. For each domain, higher scores reflect better cognition. Raw scores are converted to age and sex-corrected normalized scores. The BACS composite score is calculated as the mean of the normalized scores from the 6 subscale scores, standardized so that the mean of the BACS composite score in the healthy normative sample is 50 and the standard deviation is 10. | From baseline to Week 26 | 
| Change From Baseline to Week 26 in 10-item Drug Attitude Inventory (DAI-10) Score | The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the prescribed medication would answer as True and 4 items (2, 5, 6, and 8) that a subject who is fully adherent to the prescribed medication would answer as False. A correct answer is scored +1 and an incorrect answer is scored -1. The total score is the sum of pluses and minuses, which can range from -10 to 10 in increments of 2. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (non-adherent). Higher scores denote better adherence. | From baseline to Week 26 | 
| Change From Baseline to Week 26 in Karolinska Sleepiness Scale (KSS) Score | The KSS is a self-reported subjective measure of a subject's level of drowsiness. Respondents must choose statements that most accurately describe their level of sleepiness over the past 7 days. Scoring was based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 (very sleepy, great effort to keep awake, fighting sleep). Higher scores denoted more drowsiness. | From baseline to Week 26 |