A Double-blind, Placebo-controlled Study of the Safety and Efficacy of Paliperidone Extended Release (ER) in the Treatment of Schizophrenia in Adolescent Patients

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00518323
• Collaborator: (none)
• Enrollment: 201
• Locations: 35
• Arms: 4
• Duration (Months): 19
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, safety, and tolerability of 3 weight-based, fixed-dose groups of paliperidone extended release (ER) compared with placebo in adolescent patients between 12 to 17 years of age, who are diagnosed with schizophrenia. Paliperidone ER is an atypical antipsychotic agent approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in adults. Patients may be voluntary inpatients or outpatients at the time of the screening visit, but should have returned to their usual living situation by Day 21 of the double-blind treatment phase. The study duration is approximately 10 weeks. Patients who have completed this study or who were discontinued from this study due to lack of efficacy but have completed at least 21 days of double-blind treatment and are expected to benefit from paliperidone treatment, may enter an optional open-label safety study.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Paliperidone ER; Drug: Placebo; Drug: Paliperidone ER; Drug: Paliperidone ER	Phase 3

Detailed Description

The study is a multicenter, randomized (treatment group is assigned by chance), double-blind (neither the physician nor the patient knows which treatment group the patient is in), parallel-group, placebo controlled study. This study will enroll adolescent men and women who have schizophrenia as specified by the Diagnostic and Statistical Manual of Mental Disorders; 4th Edition (DSM-IV) diagnosis of schizophrenia (295.10, 295.20, 295.30, 295.60, and 295.90) as confirmed by the Kiddie-Sads-Present and Lifetime Version (KSADS-PL), and who should have a Positive and Negative Syndrome Scale (PANSS) score that is between 60 and 120, inclusive, at screening and baseline. Before any study related procedure is performed, the patient and his parent or legal guardian must have provided assent and signed an informed consent form, respectively. The study consists of 3 phases: a screening phase, a 6-week double-blind treatment phase with an end-of-study or early withdrawal visit, and a 1 week follow-up visit for patients who do not enter the optional open-label safety study. In the screening phase, a trained clinician will complete the K SADS-PL interview, including all 5 supplements, to confirm the DSM-IV diagnostic criteria for schizophrenia. In addition, the K-SADS-PL screening diagnostic interview items for suicide must each have a score of <=2, as follows: item a), recurrent thoughts of death; item b), suicidal thoughts; item c), suicide attempts and their seriousness; item d), suicide attempts and their lethality; and item e) self harming behavior. Women of childbearing potential will undergo a urine pregnancy test at screening, baseline, Week 4, and at end of study or upon early withdrawal from the study. Patients who are receiving prohibited medications, such as antidepressants, lithium, drugs of abuse, and alcohol, will enter a washout period during which medications will be tapered down and eventually stopped. The screening and washout phase may not exceed 21 days. In the double-blind treatment phase, at the baseline visit, the inclusion and exclusion criteria will be reviewed. Patients who continue to meet the criteria will be randomly assigned (as in the toss of a coin) to 1 of 4 dose groups. Patients weighing between 29 to <51 kilograms (kg) will receive paliperidone ER 1.5, 3.0, or 6.0 milligrams (mg) or matching placebo. Patients weighing >=51 kg will receive paliperidone ER 1.5, 6.0, or 12.0 mg or matching placebo. Patients will come to the study site for weekly visits during this phase. A follow-up visit will occur 1 week after the end of treatment for those patients who will not enter the open-label study. Efficacy and safety procedures will be performed at specified times during the study. Efficacy procedures include the administration of the PANSS, Children's Global Assessment (CGAS), Clinical Global Impression-Severity (CGI-S) and a sleep visual analog scale. Safety assessments include a physical examination (ECG measurements, vital signs, weight, height, and waist measurements), clinical laboratory testing, drug screen, Simpson and Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Tanner Staging, concomitant medications and the recording of adverse events. A Data Safety Monitoring Board will oversee the conduct of the study and review adverse event reports and laboratory test results. The total volume of blood drawn for laboratory evaluation throughout the study, including 10 milliliters (mL) for the optional pharmacogenomics testing, is approximately 66 mL for each patient. Blood samples will be collected to explore the pharmacokinetics of paliperidone in adolescent patients. The study hypothesis is that at least 1 paliperidone ER dose group will be superior to placebo in improving the symptoms of schizophrenia as measured by the change in total PANSS score from the baseline to endpoint (Week 6). Paliperidone ER 1.5, 3.0, 6.0, or 12.0 mg or matching placebo will be administered daily in the morning before 10 a.m., and at approximately the same time each day. Study drug administration should occur in a consistent manner relative to the intake of food (i.e., either before or after breakfast, or without any breakfast) throughout the study. Study drug should be swallowed whole and with water. Study drug will be administered for 6 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 201 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Double-Blind, Weight-Based, Fixed-Dose, Parallel-Group, Placebo-Controlled Study of the Efficacy and Safety of Extended Release Paliperidone for the Treatment of Schizophrenia in Adolescent Subjects, 12 to 17 Years of Age
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Paliperidone ER 1.5 mg tablet once daily for 6 weeks	Drug: Paliperidone ER; 1.5 mg tablet once daily for 6 weeks
Experimental: 002 Paliperidone ER 3 mg or 6 mg tablet once daily for 6 weeks	Drug: Paliperidone ER; 3 mg or 6 mg tablet once daily for 6 weeks
Experimental: 003 Paliperidone ER 6 mg or 12 mg tablet once daily for 6 weeks	Drug: Paliperidone ER; 6 mg or 12 mg tablet once daily for 6 weeks
Placebo Comparator: 004 Placebo Once daily for 6 weeks	Drug: Placebo; Once daily for 6 weeks

Outcome Measures

Primary Outcome Measures

1. Change in the PANSS Total Score From Baseline to the Last Postrandomization Assessment in the Double-blind Period of the Study. [6 weeks]

   The Positive and Negative Syndrome Scale (PANSS) measures the severity of psychotic symptoms of schizophrenia. Scores range from 30 to 210, where 30=best and 210=worst. The change in PANSS total score for all eligible subjects was measured from the beginning of the study to the end.

Secondary Outcome Measures

1. Change From Baseline to End Point in Clinical Global Impression-Severity (CGI-S) Scale [6 weeks]

   The CGI-S rating scale was used to assess the severity of a subject's overall clinical condition. Scores range from 1 to 7, where 1=best and 7=worst.

2. Change From Baseline to End Point in Children's Global Assessment (CGAS) Score [6 weeks]

   The CGAS score assesses psychological, social, and school functioning for children 6 to 17 years of age. Scores range from 1 to 100, where 100=best and 1=worst.

3. Change From Baseline to End Point in Sleep Visual Analog Scale (VAS) for Quality of Sleep. [6 weeks]

   The sleep VAS for sleep quality is a scale for measuring the quality of sleep experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst.

4. Change From Baseline to End Point in Sleep VAS for Daytime Drowsiness [6 weeks]

   The sleep VAS for daytime drowsiness is a scale for measuring the drowsiness experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must meet the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM

1. criteria for schizophrenia (295.10, 295.20, 295.30, 295.60, 295.90) for 1 year (the diagnosis will be established using the K-SADS-PL, including all supplements)

• Must not be a danger to themselves or others, and must have family support available to be maintained as an outpatient

• Should have had at least 1 adequate treatment with an antipsychotic before participation in this study

• Must have a PANSS score between 60 and 120, inclusive, at screening and baseline

• Weight >=29 kg

Exclusion Criteria:

• Meet the DSM-IV criteria at screening for dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, or primary substance induced psychotic disorder. Other comorbid disorders e.g., attention-deficit hyperactivity disorder (ADHD) are allowed as long as the diagnosis of schizophrenia is the primary diagnosis and the comorbid disorders in the investigator's judgment do not require medication

• Mild, moderate, or severe mental retardation (i.e., documented intelligence quotient [IQ] <70) established by previous IQ testing or history

• Women who are pregnant (as confirmed by urine pregnancy test performed at screening or baseline), planning to become pregnant or are nursing

• Have a known or suspected history of seizure disorder, or neuroleptic malignant syndrome, encephalopathic syndrome, tardive dyskinesia, or insulin dependent diabetes mellitus

• Presence of any significant or unstable cardiovascular, respiratory, renal, hepatic, hematologic, endocrine, immunologic, or other systemic disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Cerritos	California	United States
2		Fountain Valley	California	United States
3		San Diego	California	United States
4		Santa Ana	California	United States
5		Washington	District of Columbia	United States
6		Lake Charles	Louisiana	United States
7		Boston	Massachusetts	United States
8		Cleveland	Ohio	United States
9		Portsmouth	Virginia	United States
10		Spokane	Washington	United States
11		Bangalore		India
12		Chennai		India
13		Hyderabad Andra Pradesh		India
14		Hyderabad		India
15		Mangalore		India
16		New Delhi		India
17		Varanasi		India
18		Bucharest		Romania
19		Ekaterinburg Na		Russian Federation
20		Kazan		Russian Federation
21		Moscow N/A		Russian Federation
22		Moscow Russia		Russian Federation
23		Nizhniy Novgorod		Russian Federation
24		Saratov N/A		Russian Federation
25		Smolensk Region N/A		Russian Federation
26		St Petersburg		Russian Federation
27		St-Petersburg		Russian Federation
28		Stavropol Na		Russian Federation
29		Tomsk Na		Russian Federation
30		Yaroslavl		Russian Federation
31		Glevakha		Ukraine
32		Kharkov		Ukraine
33		Kiev		Ukraine
34		Odessa		Ukraine
35		Simferopol		Ukraine

Sponsors and Collaborators

• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A double-blind, placebo-controlled study of the safety and efficacy of paliperidone extended release (ER) in the treatment of schizophrenia in adolescent patients

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00518323
• Other Study ID Numbers: CR002368; R076477PSZ3001
• First Posted: Aug 20, 2007
• Last Update Posted: Apr 16, 2014
• Last Verified: Nov 1, 2010

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Schizophrenia; Antipsychotic
• Additional relevant MeSH terms: Schizophrenia; Paliperidone Palmitate

Study Results

Participant Flow

Recruitment Details	Recruitment started 8 August 2007 in medical clinics located around the world. The study ended on 30 March 2009.
Pre-assignment Detail	Subjects who were eligible for the study had their current disallowed psychotropic medications washed out prior to assignment to treatment groups. Subjects who violated inclusion criteria before assignment (eg, because they continued to take a disallowed medication) were to be removed from the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Period Title: Overall Study
STARTED	54	48	48	51
COMPLETED	35	40	37	26
NOT COMPLETED	19	8	11	25

Baseline Characteristics

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo	Total
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)	Total of all reporting groups
Overall Participants	54	48	48	51	201
Age (Count of Participants)
<=18 years	54 100%	48 100%	48 100%	51 100%	201 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.1 (1.50)	15.3 (1.60)	15.5 (1.60)	15.7 (1.40)	15.4 (1.53)
Sex: Female, Male (Count of Participants)
Female	24 44.4%	17 35.4%	14 29.2%	28 54.9%	83 41.3%
Male	30 55.6%	31 64.6%	34 70.8%	23 45.1%	118 58.7%
Region of Enrollment (participants) [Number]
United States	8 14.8%	6 12.5%	7 14.6%	9 17.6%	30 14.9%
Ukraine	9 16.7%	8 16.7%	9 18.8%	8 15.7%	34 16.9%
Romania	2 3.7%	3 6.3%	3 6.3%	2 3.9%	10 5%
Russian Federation	22 40.7%	20 41.7%	19 39.6%	21 41.2%	82 40.8%
India	13 24.1%	11 22.9%	10 20.8%	11 21.6%	45 22.4%

Outcome Measures

1. Primary Outcome

Title	Change in the PANSS Total Score From Baseline to the Last Postrandomization Assessment in the Double-blind Period of the Study.
Description	The Positive and Negative Syndrome Scale (PANSS) measures the severity of psychotic symptoms of schizophrenia. Scores range from 30 to 210, where 30=best and 210=worst. The change in PANSS total score for all eligible subjects was measured from the beginning of the study to the end.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Measure Participants	54	48	47	51
Mean (Standard Deviation) [units on a scale]	-9.8 (16.31)	-17.3 (14.33)	-13.8 (15.74)	-7.9 (20.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali ER Low, Placebo
	Comments	If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.508
	Comments	The p value was associated with the closed testing procedure using Dunnett's test.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.1
	Confidence Interval	() 95%; -8.36 to 4.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.17
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pali ER Medium, Placebo
	Comments	If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	The p value was associated with the closed testing procedure using Dunnett's test.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.1
	Confidence Interval	() 95%; -16.58 to -3.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.27
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pali ER High, Placebo
	Comments	If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments	The p value was associated with the closed testing procedure using Dunnett's test.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.6
	Confidence Interval	() 95%; -13.07 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.29
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

2. Secondary Outcome

Title	Change From Baseline to End Point in Clinical Global Impression-Severity (CGI-S) Scale
Description	The CGI-S rating scale was used to assess the severity of a subject's overall clinical condition. Scores range from 1 to 7, where 1=best and 7=worst.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Measure Participants	54	48	47	51
Median (Full Range) [units on a scale]	0.0	-1.0	-1.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali ER Low, Placebo
	Comments	Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.968
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pali ER Medium, Placebo
	Comments	Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pali ER High, Placebo
	Comments	Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Change From Baseline to End Point in Children's Global Assessment (CGAS) Score
Description	The CGAS score assesses psychological, social, and school functioning for children 6 to 17 years of age. Scores range from 1 to 100, where 100=best and 1=worst.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Measure Participants	54	48	47	51
Mean (Standard Deviation) [units on a scale]	4.4 (10.72)	13.1 (12.07)	8.6 (11.18)	5.0 (13.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali ER Low, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.846
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	() 95%; -4.54 to 3.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.10
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pali ER Medium, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.6
	Confidence Interval	() 95%; 4.28 to 12.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.17
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pali ER High, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.0
	Confidence Interval	() 95%; -0.28 to 8.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.18
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to End Point in Sleep Visual Analog Scale (VAS) for Quality of Sleep.
Description	The sleep VAS for sleep quality is a scale for measuring the quality of sleep experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Measure Participants	54	48	47	50
Mean (Standard Deviation) [units on a scale]	6.6 (24.57)	16.0 (27.06)	14.4 (22.72)	-0.3 (34.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali ER Low, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.1
	Confidence Interval	() 95%; -0.29 to 16.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.27
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pali ER Medium, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.8
	Confidence Interval	() 95%; 8.08 to 25.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.40
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pali ER High, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	13.5
	Confidence Interval	() 95%; 4.76 to 22.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.43
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to End Point in Sleep VAS for Daytime Drowsiness
Description	The sleep VAS for daytime drowsiness is a scale for measuring the drowsiness experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.

Arm/Group Title	Pali ER Low	Pali ER Medium	Pali ER High	Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above	Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)	Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
Measure Participants	54	48	47	50
Mean (Standard Deviation) [units on a scale]	-6.2 (24.69)	-7.2 (25.22)	1.0 (29.55)	-2.8 (30.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali ER Low, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.237
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.9
	Confidence Interval	() 95%; -13.11 to 3.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.15
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pali ER Medium, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.7
	Confidence Interval	() 95%; -15.15 to 1.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.28
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pali ER High, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.574
	Comments	Comparison with placebo was without multiplicity adjustment.
	Method	ANCOVA
	Comments	Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	() 95%; -11.00 to 6.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.34
	Estimation Comments

Adverse Events

Arm/Group Title	Pali ER Low		Pali ER Medium		Pali ER High		Placebo
Arm/Group Description	Paliperidone ER 1.5 mg for subjects weighing 29 kg and above		Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)		Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
All Cause Mortality
	Pali ER Low		Pali ER Medium		Pali ER High		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Pali ER Low		Pali ER Medium		Pali ER High		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/54 (3.7%)		1/48 (2.1%)		1/48 (2.1%)		1/51 (2%)
Gastrointestinal disorders
Mallory-Weiss syndrome	0/54 (0%)		1/48 (2.1%)		0/48 (0%)		0/51 (0%)
Psychiatric disorders
Schizophrenia	1/54 (1.9%)		0/48 (0%)		1/48 (2.1%)		0/51 (0%)
Agitation	1/54 (1.9%)		0/48 (0%)		0/48 (0%)		0/51 (0%)
Psychotic disorder	0/54 (0%)		0/48 (0%)		0/48 (0%)		1/51 (2%)
Other (Not Including Serious) Adverse Events
	Pali ER Low		Pali ER Medium		Pali ER High		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/54 (35.2%)		20/48 (41.7%)		33/48 (68.8%)		24/51 (47.1%)
Cardiac disorders
Tachycardia	0/54 (0%)		2/48 (4.2%)		4/48 (8.3%)		0/51 (0%)
Gastrointestinal disorders
Nausea	0/54 (0%)		0/48 (0%)		4/48 (8.3%)		6/51 (11.8%)
Vomiting	0/54 (0%)		3/48 (6.3%)		4/48 (8.3%)		5/51 (9.8%)
Investigations
Weight increased	4/54 (7.4%)		2/48 (4.2%)		1/48 (2.1%)		0/51 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/54 (1.9%)		0/48 (0%)		0/48 (0%)		3/51 (5.9%)
Nervous system disorders
Somnolence	3/54 (5.6%)		7/48 (14.6%)		10/48 (20.8%)		1/51 (2%)
Akathisia	2/54 (3.7%)		4/48 (8.3%)		8/48 (16.7%)		0/51 (0%)
Headache	5/54 (9.3%)		3/48 (6.3%)		5/48 (10.4%)		2/51 (3.9%)
Cogwheel rigidity	0/54 (0%)		0/48 (0%)		4/48 (8.3%)		0/51 (0%)
Dystonia	1/54 (1.9%)		1/48 (2.1%)		4/48 (8.3%)		0/51 (0%)
Tremor	1/54 (1.9%)		4/48 (8.3%)		4/48 (8.3%)		0/51 (0%)
Psychiatric disorders
Insomnia	5/54 (9.3%)		3/48 (6.3%)		6/48 (12.5%)		11/51 (21.6%)
Anxiety	0/54 (0%)		0/48 (0%)		4/48 (8.3%)		2/51 (3.9%)
Schizophrenia	5/54 (9.3%)		0/48 (0%)		2/48 (4.2%)		4/51 (7.8%)
Agitation	3/54 (5.6%)		1/48 (2.1%)		0/48 (0%)		2/51 (3.9%)

Limitations/Caveats

No information about longer-term (ie, >6 weeks) efficacy and safety in adolescents or in young (<12 years) children with schizophrenia. Results with doses less than 1.5 mg or more than 12 mg cannot be extrapolated from the data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.