Open-label Study of Flexible-dose Paliperidone ER (Extended Release) to Treat Adolescent Schizophrenia.

A 6-Month, Open-Label, Single-Arm Safety Study of Flexibly Dosed Paliperidone Extended Release (1.5 - 12 mg/Day) in the Treatment of Adolescents (12 to 17 Years of Age) With Schizophrenia

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00488319

Enrollment

400

Registered

2007-06-20

Start date

2007-06-30

Completion date

2012-07-31

Last updated

2017-02-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dementia Praecox, Psychotic Disorders, Schizophrenia, Schizophrenic Disorders

Keywords

Schizophrenia, Adolescent, Paliperidone, Antipsychotic agents, Antipsychotic drugs, Psychosis.

Brief summary

The purpose of this open-label study is to evaluate the long-term (6-month) safety and tolerability of extended-release paliperidone, an atypical antipsychotic, given in flexible dosages to adolescents with schizophrenia.

Detailed description

This is a 6-month, open-label study (the patient, investigator, and sponsor know the study drug and dosage being taken by the patient) of the safety and tolerability of flexible-dose (1.5 to 12mg per day), extended-release (ER) paliperidone in adolescents with a diagnosis of schizophrenia. Patients who have completed study R076477PSZ3001 or who discontinued from that study because of lack of efficacy but completed a minimum of 21 days of the study may enter this study. Patients may also enter this study directly without participating in R076477PSZ3001. This study consists of a 21-day screening and washout phase (to discontinue and wash out any medication not allowed in the study), an open-label treatment phase of up to 26 weeks during which all patients will take oral paliperidone ER every day, and a post-treatment phase consisting of a follow-up visit completed 1 week after a patient has received the final dose of paliperidone ER. The study, including the screening and posttreatment phase, will last approximately 30 weeks. Screening and washout may be conducted while a patient is either an inpatient or an outpatient. Safety will be assessed by laboratory measurements (chemistry, liver function tests, hematology, hormone, lipid assessments, prolactin \[blinded\], urinalysis, and urine drug screens); body weight, height, and waist circumference measurements; ECGs; and physical examinations (including Tanner staging). The Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson Angus Rating Scale (SAS) will be used to assess extrapyramidal symptoms (EPS) and dyskinesias. Adverse events will be monitored including psychiatric adverse events of interest (i.e., suicide and related phenomena, homicidal ideation, depressed mood, and worsening of psychosis) that may be associated with paliperidone ER in this population. The primary aim of this study is to evaluate the long-term (6-month) safety and tolerability of paliperidone ER in adolescents with schizophrenia. As exploratory secondary aims, the study will assess the effect of paliperidone ER on the long-term symptoms of schizophrenia as measured by the changes in the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores, the global improvement in severity of illness as measured by the Clinical Global Impression-Severity (CGI-S) scale, the benefits in psychological, social, and school functioning as measured by the Children's Global Assessment Scale (CGAS), the changes in multiple domains of cognitive functioning measured by the modified Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) assessment battery, and the effect on sleep as measured by the sleep Visual Analog Scale (VAS). Patients begin the study at 6.0 mg/day of oral paliperidone ER. If a higher dosage is needed, the dosage will be increased (in increments of 3 mg/day not more frequently than once every 5 days) to 12 mg/day. If the 6.0 mg/day dosage is not well tolerated, the dosage may be decreased (not more frequently than once every 5 days) to 3.0 mg/day or 1.5 mg/day. Patients will be dosed for up to 6 months.

Interventions

DRUGPaliperidone ER

1.5 to 12 mg tablet once daily for 6 months

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to 17 Years

Healthy volunteers

Inclusion criteria

* Meets the DSM-IV criteria for schizophrenia, otherwise physically healthy * Weight \>=63.9 pounds (29 kg) * Must not be a danger to self or others and must have family support available to be maintained as outpatients * Responsible adult must be available to accompany the patient to the investigational site at each visit.

Exclusion criteria

* Meets the DSM-IV criteria for dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, or primary substance-induced psychotic disorder * mild, moderate, or severe mental retardation * History of substance dependence (including alcohol, but excluding nicotine and caffeine) according to the DSM-IV criteria in the 3 months before screening * pregnancy (for females) * History or presence of circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death in association with the use of drugs that prolong the QTc interval.

Design outcomes

Primary

Measure	Time frame	Description
The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Up to 2 years	A serious adverse event as defined by the International Conference on Harmonisation (ICH) is any untoward medical occurrence that at any dose results in death, is life-threatening (the subject was at risk of death at the time of the even; it does not refer to an event that hypothetically might have caused death if it were more severe), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Secondary

Measure	Time frame	Description
Change From Open-label Baseline to Open-label Endpoint in the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Based on Marder Factors - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	Neuropsychiatric symptoms of schizophrenia were assessed using the 30-item PANSS scale. PANSS scale provides a total score (sum of scores of all 30 items) and scores for 3 subscales, ie, positive (7 items), negative (7 items), and general psychopathology (16 items) subscales. Each item is scored on a scale of 1 (absent) to 7 (extreme). Positive Factor Score (range: 8 to 56): sum of select scores from positive, negative, and general psychopathology subscales. Negative Factor Score (range: 7 to 49): sum of select scores from negative and general psychopathology subscales. Disorganized Thoughts Factor Score (range: 7 to 49): sum of select scores from positive, negative, and general psychopathology subscales. Uncontrolled Hostility/Excitement Factor Score (range: 4 to 28): sum of select scores from positive and general psychopathology subscales. Anxiety/Depression Factor Score (range: 4 to 28): sum of select scores from general psychopathology subscale. Higher scores indicate worsening.
Change From Open-label Baseline to Open-label Endpoint in the Clinical Global Impression Severity (CGI-S) Scale - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to Normal, not at all ill and a rating of 7 is equivalent to Among the most extremely ill participants. Higher scores indicate worsening.
Change From Open-label Baseline to Open-label Endpoint in the Children's Global Assessment Scale (CGAS) - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	The CGAS is a 100 point rating scale which measures the psychological, social, and school functioning for children 6 to 17 years of age. The score ranges from 1 to 100, divided into 10 equal intervals to rate the impairment level of general functioning (poor to superior functioning). Higher scores denote better functioning.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Scores - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	The PANSS is a medical scale that assesses various symptoms of schizophrenia. The symptoms are rated on a 7-point scale from 1 (absent) to 7 (extreme psychopathology). The total score is the sum of all 30 PANSS items, with a range of 30 (absent) to 210 (extreme ill).
Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.
Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Quality of Sleep - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	Sleep VAS is a self administered scale that rates the quality of sleep and daytime drowsiness. Participants make a mark on a line to represent how well they have slept in the previous 7 days (very badly to very well) and how often they have felt drowsy within the previous 7 days (not at all to all the time). The score for each item ranges from 0 to 100 mm. For quality of sleep, a score of 0 indicates Very badly and a score of 100 indicates Very well. For daytime drowsiness, a score of 0 indicates Not at all and a score of 100 indicates All the time. Improvement of the condition is indicated by the positive change for the quality of sleep and the negative change for the daytime drowsiness.
Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Daytime Drowsiness - Last Observation Carried Forward	Baseline, Week 104 or the last post-baseline assessment	Sleep VAS is a self administered scale that rates the quality of sleep and daytime drowsiness. Participants make a mark on a line to represent how well they have slept in the previous 7 days (very badly to very well) and how often they have felt drowsy within the previous 7 days (not at all to all the time). The score for each item ranges from 0 to 100 mm. For quality of sleep, a score of 0 indicates Very badly and a score of 100 indicates Very well. For daytime drowsiness, a score of 0 indicates Not at all and a score of 100 indicates All the time. Improvement of the condition is indicated by the positive change for the quality of sleep and the negative change for the daytime drowsiness.
Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward	Baseline, Week 24	A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.

Countries

Belgium, Bulgaria, Estonia, Finland, India, Poland, Romania, Russia, South Korea, Ukraine, United States

Participant flow

Recruitment details

This study evaluated the long-term (2 year) safety and tolerability of paliperidone extended release (ER) in adolescent patients with schizophrenia. This study was conducted from 27 June 2007 to 18 July 2012 at 55 centers in 10 countries. A total of 400 patients received at least 1 dose of the study drug and were included in the safety analysis.

Pre-assignment details

Patients enrolled in this study came from 3 different sources: patients who enrolled directly, patients who were randomly assigned to placebo in the R076477PSZ3001 (NCT00518323) study, and patients who were randomly assigned to paliperidone ER in the R076477PSZ3001 (NCT00518323) study.

Participants by arm

Arm	Count
Placebo/Paliperidone Patients in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.	39
Paliperidone (Double-blind)/Paliperidone Patients in this group were previously assigned to paliperidone extended-release in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.	118
Paliperidone (No Double-blind)/Paliperidone Patients in this group were directly enrolled into the study and started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.	243
Total	400

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	1	2	23
Overall Study	Lack of Efficacy	6	12	27
Overall Study	Lost to Follow-up	3	5	16
Overall Study	Other reasons for withdrawal	0	4	12
Overall Study	Withdrawal by Subject	5	20	44

Baseline characteristics

Characteristic	Placebo/Paliperidone	Paliperidone (Double-blind)/Paliperidone	Paliperidone (No Double-blind)/Paliperidone	Total
Age, Categorical <=18 years	39 Participants	118 Participants	243 Participants	400 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Continuous	15.8 years STANDARD_DEVIATION 1.48	15.3 years STANDARD_DEVIATION 1.59	15.3 years STANDARD_DEVIATION 1.53	15.4 years STANDARD_DEVIATION 1.55
Gender Female	21 Participants	44 Participants	92 Participants	157 Participants
Gender Male	18 Participants	74 Participants	151 Participants	243 Participants
Region of Enrollment Bulgaria	0 participants	0 participants	6 participants	6 participants
Region of Enrollment Estonia	0 participants	0 participants	3 participants	3 participants
Region of Enrollment Finland	0 participants	0 participants	3 participants	3 participants
Region of Enrollment India	6 participants	23 participants	35 participants	64 participants
Region of Enrollment Korea	0 participants	0 participants	40 participants	40 participants
Region of Enrollment Poland	0 participants	0 participants	47 participants	47 participants
Region of Enrollment Romania	2 participants	8 participants	10 participants	20 participants
Region of Enrollment Russia	18 participants	51 participants	40 participants	109 participants
Region of Enrollment Ukraine	8 participants	22 participants	18 participants	48 participants
Region of Enrollment United States of America	5 participants	14 participants	41 participants	60 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	26 / 39	74 / 118	192 / 243
serious Total, serious adverse events	9 / 39	4 / 118	46 / 243

Outcome results

Primary

The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability

A serious adverse event as defined by the International Conference on Harmonisation (ICH) is any untoward medical occurrence that at any dose results in death, is life-threatening (the subject was at risk of death at the time of the even; it does not refer to an event that hypothetically might have caused death if it were more severe), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Time frame: Up to 2 years

Population: The safety analysis set was used for the safety analyses and included all enrolled participants who received at least 1 dose of the open-label study drug as recorded on the electronic case report form. This population was considered as evaluable participants.

Arm	Measure	Group	Value (NUMBER)
Placebo/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	One or More Serious TEAEs	9 Number of Participants
Placebo/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Treatment Emergent Adverse Events (TEAEs)	32 Number of Participants
Placebo/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Possibly-related TEAEs	24 Number of Participants
Paliperidone (Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	One or More Serious TEAEs	4 Number of Participants
Paliperidone (Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Possibly-related TEAEs	61 Number of Participants
Paliperidone (Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Treatment Emergent Adverse Events (TEAEs)	88 Number of Participants
Paliperidone (No Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Treatment Emergent Adverse Events (TEAEs)	221 Number of Participants
Paliperidone (No Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Possibly-related TEAEs	185 Number of Participants
Paliperidone (No Double-blind)/Paliperidone	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	One or More Serious TEAEs	46 Number of Participants
Total	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	One or More Serious TEAEs	59 Number of Participants
Total	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Treatment Emergent Adverse Events (TEAEs)	341 Number of Participants
Total	The Number of Participants Who Experienced Adverse Events as a Measure of Safety and Tolerability	Possibly-related TEAEs	270 Number of Participants

Secondary

Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward

A comprehensive neuropsychological examination that measures different domains of cognitive functioning is provided. They are either assessed as T-scores \[mean=50, SD=10 range 1-100\]; z-scores \[mean=0, SD=1, and can be positive or negative\] or scaled scores \[mean=10, SD=3, and can be positive or negative\]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance.

Time frame: Baseline, Week 24

Population: The open-label intent-to-treat analysis set was used for the efficacy analyses. All enrolled participants who received at least 1 dose of open-label study drug and had both the baseline and at least 1 postbaseline assessment in the open-label phase were included in this analysis set.

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward	0 Scores on a scale	—
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward	0.6 Scores on a scale	Standard Deviation 3.57
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward	1.7 Scores on a scale	Standard Deviation 1.36
Total	Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - Last Observation Carried Forward	1.3 Scores on a scale	Standard Deviation 2.33

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward	1.9 Scores on a scale	Standard Deviation 3.25
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward	1.5 Scores on a scale	Standard Deviation 2.54
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward	0.1 Scores on a scale	Standard Deviation 2.6
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - Last Observation Carried Forward	0.8 Scores on a scale	Standard Deviation 2.75

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward	0.9 Scores on a scale	Standard Deviation 2.42
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward	0.8 Scores on a scale	Standard Deviation 2.81
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward	0.8 Scores on a scale	Standard Deviation 2.71
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - Last Observation Carried Forward	0.8 Scores on a scale	Standard Deviation 2.71

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - Last Observation Carried Forward	0.2 Scores on a scale	Standard Deviation 2.67
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - Last Observation Carried Forward	0.7 Scores on a scale	Standard Deviation 2.53
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - Last Observation Carried Forward	0.5 Scores on a scale	Standard Deviation 2.57

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward	4.3 Scores on a scale	Standard Deviation 11.13
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward	4.6 Scores on a scale	Standard Deviation 11.09
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward	7.0 Scores on a scale	Standard Deviation 13.16
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - Last Observation Carried Forward	5.9 Scores on a scale	Standard Deviation 12.32

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Dominant Hand	0.2 Scores on a scale	Standard Deviation 1.15
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Non Dominant Hand	0.2 Scores on a scale	Standard Deviation 1.2
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Non Dominant Hand	0.4 Scores on a scale	Standard Deviation 2.05
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Dominant Hand	0.1 Scores on a scale	Standard Deviation 1.65
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Dominant Hand	0.3 Scores on a scale	Standard Deviation 1.36
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Non Dominant Hand	0.2 Scores on a scale	Standard Deviation 1.55
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Dominant Hand	0.2 Scores on a scale	Standard Deviation 1.44
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - Last Observation Carried Forward	Finger Tapping Non Dominant Hand	0.3 Scores on a scale	Standard Deviation 1.69

Secondary

Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward

Time frame: Baseline, Week 24

Population: The open label intent-to-treat analysis set was used for the efficacy analyses. All enrolled participants who received at least 1 dose of open label study drug and had both the baseline and at least 1 postbaseline assessment in the open label phase were included in this analysis set.

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward	3.4 Scores on a scale	Standard Deviation 7.04
Paliperidone (Double-blind)/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward	4.1 Scores on a scale	Standard Deviation 6.68
Paliperidone (No Double-blind)/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward	5.6 Scores on a scale	Standard Deviation 9.2
Total	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - Last Observation Carried Forward	4.9 Scores on a scale	Standard Deviation 8.23

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward	0.0 Scores on a scale	Standard Deviation 20.82
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward	3.6 Scores on a scale	Standard Deviation 11.9
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward	6.2 Scores on a scale	Standard Deviation 14.41
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - Last Observation Carried Forward	4.7 Scores on a scale	Standard Deviation 14.62

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward	0.3 Scores on a scale	Standard Deviation 1.48
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward	0.2 Scores on a scale	Standard Deviation 1.07
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward	0.5 Scores on a scale	Standard Deviation 1.09
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - Last Observation Carried Forward	0.4 Scores on a scale	Standard Deviation 1.14

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward	0.2 Scores on a scale	Standard Deviation 1.23
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward	0.1 Scores on a scale	Standard Deviation 0.82
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward	0.2 Scores on a scale	Standard Deviation 0.9
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - Last Observation Carried Forward	0.2 Scores on a scale	Standard Deviation 0.91

Secondary

Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward	1.8 Scores on a scale	Standard Deviation 1.06
Paliperidone (Double-blind)/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward	-2.3 Scores on a scale	Standard Deviation 4.97
Paliperidone (No Double-blind)/Paliperidone	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward	1.5 Scores on a scale	Standard Deviation 7.66
Total	Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - Last Observation Carried Forward	0.0 Scores on a scale	Standard Deviation 6.69

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward	29.0 Scores on a scale	—
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward	3.5 Scores on a scale	Standard Deviation 12.29
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward	8.2 Scores on a scale	Standard Deviation 12.19
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - Last Observation Carried Forward	7.2 Scores on a scale	Standard Deviation 12.7

Secondary

Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward

Time frame: Baseline, Week 24

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward	-0.5 Scores on a scale	Standard Deviation 1.56
Paliperidone (Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward	-0.3 Scores on a scale	Standard Deviation 2.02
Paliperidone (No Double-blind)/Paliperidone	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward	0.3 Scores on a scale	Standard Deviation 2.39
Total	Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - Last Observation Carried Forward	0.0 Scores on a scale	Standard Deviation 2.21

Secondary

Change From Open-label Baseline to Open-label Endpoint in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Scores - Last Observation Carried Forward

The PANSS is a medical scale that assesses various symptoms of schizophrenia. The symptoms are rated on a 7-point scale from 1 (absent) to 7 (extreme psychopathology). The total score is the sum of all 30 PANSS items, with a range of 30 (absent) to 210 (extreme ill).