Effectiveness and Safety of 3 Fixed Doses (25 mg eq., 100 mg eq., and 150 mg eq.) of Paliperidone Palmitate in Patients With Schizophrenia

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00590577
• Collaborator: (none)
• Enrollment: 652
• Locations: 66
• Arms: 4
• Duration (Months): 12
• Patients Per Site: 9.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The primary objectives of this study are to evaluate the efficacy and safety of 3 fixed doses of paliperidone palmitate administered i.m. after an initial loading dose of 150 mg eq. in the deltoid muscle followed by either deltoid or gluteal injections for a total of 13 weeks of treatment as compared with placebo in patients with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Paliperidone palmitate 25 mg eq.; Drug: Paliperidone palmitate 150 mg eq.; Drug: Placebo; Drug: Paliperidone palmitate 100 mg eq.	Phase 3

Detailed Description

The primary hypothesis is that, after an initial 150 mg eq. loading dose in the deltoid muscle followed by either deltoid or gluteal injections in patients with schizophrenia, paliperidone palmitate (25, 100, or 150 mg eq.) is superior to placebo as measured by the change in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score over a 13-week period.This is a randomized, double blind, placebo-controlled, parallel group, multicenter, dose-response study of men and women who have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia. The secondary objectives are to: Assess the benefits in personal and social functioning (key secondary endpoint) associated with the use of paliperidone palmitate compared with placebo, Assess the global improvement in severity of illness associated with the use of paliperidone palmitate compared with placebo, Assess the dose-response and exposure-response relationship of paliperidone palmitate The study includes a screening period of up to 7 days and a 13 week double-blind treatment period. The screening period includes washout of disallowed psychotropic medications. Subjects without source documentation of previous exposure to at least 2 doses of oral risperidone, or paliperidone ER, or one dose of i.m. RISPERDAL CONSTA, or paliperidone palmitate will be given 4 to 6 days of paliperidone ER 6 mg/day for tolerability testing. Patients who have source documentation of previous exposure to the above medications and are currently taking another antipsychotic regimen will continue their current treatment through Day -1. At the beginning of the double-blind treatment period, subjects will be randomly assigned in equal numbers to 1 of 4 treatment groups (an initial loading dose of 150 mg eq. of paliperidone palmitate given by deltoid injection followed by 3 fixed i.m. doses of paliperidone palmitate [25, 100, or 150 mg eq.] on Days 8, 36, and 64 or placebo given in the same manner). Note: The choice of the injection site (deltoid or gluteal) for all remaining injections after the initial loading dose will be at the discretion of the investigator. The entire study, including the screening period, will last approximately 14 weeks.Samples for pharmacokinetic (PK) evaluation will be collected at designated time points. Effectiveness and safety will be evaluated periodically throughout the study. A pharmacogenomic blood sample (10 mL) will be collected from patients who give separate written informed consent for this part of the study (where local regulations permit). This will allow for pharmacogenomic research, as necessary. Participation in pharmacogenomic research is optional. Approximately 105 to 115 mL of whole blood will be collected during the study. Patients randomly assigned to paliperidone palmitate will receive i.m. injections of paliperidone palmitate (150 mg eq. deltoid injection of paliperidone palmitate on Day 1, followed by 25, 100, or 150 mg eq. of paliperidone palmitate i.m. on Days 8, 36, and 64). Patients randomly assigned to placebo will receive a deltoid injection of placebo on Day 1 followed by placebo on Days 8, 36, and 64.

Study Design

• Study Type: Interventional
• Actual Enrollment: 652 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose Response Study to Evaluate the Efficacy and Safety of 3 Fixed Doses (25 mg eq., 100 mg eq., and 150 mg eq.) of Paliperidone Palmitate in Subjects With Schizophrenia
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Paliperidone palmitate 25 mg eq. Paliperidone palmitate 150 mg eq. i.m. Day 1 and 25 mg eq. i.m. Days 8 36 64	Drug: Paliperidone palmitate 25 mg eq.; Paliperidone palmitate 150 mg eq. i.m. Day 1 and 25 mg eq. i.m. Days 8, 36, 64
Experimental: 002 Paliperidone palmitate 100 mg eq. Paliperidone palmitate 150 mg eq. i.m. Day 1 and 100 mg eq. i.m. Days 8 36 64	Drug: Paliperidone palmitate 100 mg eq.; Paliperidone palmitate 150 mg eq. i.m. Day 1 and 100 mg eq. i.m. Days 8, 36, 64
Experimental: 003 Paliperidone palmitate 150 mg eq. Paliperidone palmitate 150 mg eq. i.m. Days 1 8 36 64	Drug: Paliperidone palmitate 150 mg eq.; Paliperidone palmitate 150 mg eq. i.m. Days 1, 8, 36, 64
Placebo Comparator: 004 Placebo Placebo i.m. Days 1 8 36 64	Drug: Placebo; Placebo i.m. Days 1, 8, 36, 64

Outcome Measures

Primary Outcome Measures

1. Change in Positive and Negative Syndrome Scale (PANSS) Total Score From Baseline to Week 13 or the Last Post-baseline Assessment [Baseline to 13 weeks or the last post-baseline assessment]

   The 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 Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.

Secondary Outcome Measures

1. Change in Personal and Social Performance Scale (PSP) Score From Baseline to Week 13 or the Last Post-baseline Assessment. [Baseline to 13 weeks or the last post-baseline assessment]

   The PSP scale measures the degree of normal function of a subject in interpersonal relationships and social interactions. Scores range from 1 to 100, where 1 is worst and 100 is best. The average change in PSP score for all eligible subjects was measured from the beginning of the study to Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.

2. Change in Clinical Global Impression-Severity (CGI-S) Scores From Baseline to Week 13 or the Last Post-baseline Assessment [Baseline to 13 weeks or the last post-baseline assessment]

   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. The change in CGI-S score for all eligible subjects was measured from the beginning of the study to Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Met diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) for at least 1 year before screening. Prior medical records, written documentation or verbal information obtained from previous psychiatric providers obtained by the investigator must be consistent with the diagnosis of schizophrenia

• A total PANSS score at screening of between 70 and 120, inclusive and at baseline of between 60 and 120, inclusive

• Body mass index (BMI)

• i.e., [weight (kg)]/[height (m)]², of >17.0 kg/m2

• Women must be postmenopausal for at least 2 years, surgically sterile, abstinent, or agree to practice an effective method of birth control if they are sexually active before entry and throughout the study. Effective methods of birth control include: prescription hormonal contraceptives, intrauterine device, double-barrier method, and male partner sterilization. Women of childbearing potential must have a negative urine pregnancy test at baseline, before receiving a dose of study drug

• Is able and willing to meet or perform study requirements (e.g., answer self-administered questionnaires). If a patient is unable to read the questions, study personnel may read documents and the patient may then mark his or her choice

• Patients in the US must be able to understand spoken English to permit adequate ratings by the blinded central rater

Exclusion Criteria:

• Primary diagnosis other than schizophrenia

• Patients who are unable to provide their own consent or who are currently involuntarily committed to psychiatric hospitalization

• DSM-IV diagnosis of active substance dependence within 3 months before the screening evaluation (nicotine and caffeine dependence are not exclusionary)

• History of treatment resistance as defined by failure to respond to 2 adequate studies of different antipsychotic medications

• an adequate study is defined as a minimum of 4 weeks at the patient's maximum tolerated dose

• Relevant history of or current presence of any significant or unstable cardiovascular, respiratory, neurological (including seizures or significant cerebrovascular), renal, hepatic, hematologic, endocrine, immunologic, morbid obesity (BMI>=40), or other systemic disease

• History of any severe preexisting gastrointestinal narrowing (pathologic or iatrogenic) or inability to swallow the oral tolerability medication whole with the aid of water for patients requiring oral tolerability testing

• Biochemistry, hematology or urinalysis test results that are not within the laboratory's normal reference range and are deemed to be clinically significant by the investigator

• History or evidence of clinically significant hepatic disease (including aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >2 times the upper limit of normal) at screening

• History of neuroleptic malignant syndrome

• Significant risk of suicidal, homicidal or violent ideation or behavior as clinically assessed by the investigator

• History of life threatening allergic reaction to any drug

• Known or suspected hypersensitivity or intolerance of risperidone, paliperidone, Intralipid (placebo) or any of their excipients (e.g., soybean oil, egg yolks, phospholipids, glycerol)

• Exposure to an experimental drug, experimental biologic, or experimental medical device within 6 months before screening or prior randomization into this study

• Enrollment in 2 or more clinical research studies in the previous year or one or more clinical research studies in the previous 6 months (non intervention, observational, and retrospective studies excluded)

• History of any active malignancy within the previous 5 years, with the exception of excised basal cell carcinomas

• A woman who is pregnant, breast-feeding, or planning to become pregnant during the study period

• Employee of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator

• Treatment with any of the following disallowed therapies: an injectable antipsychotic within 1 injection cycle before screening, an injection of RISPERDAL CONSTA within 6 weeks of screening, electroconvulsive therapy within 60 days before screening, previous injection of paliperidone palmitate within the past 10 months before baseline, use of clozapine within 3 months before baseline, nonselective or irreversible monoamine oxidase inhibitor antidepressants within 30 days before screening: other antidepressants unless patient has been on a stable dose for at least 30 days before screening, mood stabilizers and beta-blockers must be washed out by the beginning of the study

• History or presence of circumstances that may increase the risk of the occurrence of serious illness or death in association with the use of drugs that affect heart rhythm

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Anaheim	California	United States
2		Cerritos	California	United States
3		Escondido	California	United States
4		Glendale	California	United States
5		La Palma	California	United States
6		Los Angeles	California	United States
7		National City	California	United States
8		San Diego	California	United States
9		Santa Ana	California	United States
10		Jacksonville	Florida	United States
11		Kissimmee	Florida	United States
12		Miami	Florida	United States
13		North Miami	Florida	United States
14		Atlanta	Georgia	United States
15		Hoffman Estates	Illinois	United States
16		Kingsport	Indiana	United States
17		Wichita	Kansas	United States
18		Lake Charles	Louisiana	United States
19		Shreveport	Louisiana	United States
20		Baltimore	Maryland	United States
21		Rockville	Maryland	United States
22		Cedarhurst	New York	United States
23		New York	New York	United States
24		Olean	New York	United States
25		Cincinnati	Ohio	United States
26		Moore	Oklahoma	United States
27		Charleston	South Carolina	United States
28		Austin	Texas	United States
29		Houston	Texas	United States
30		San Antonio	Texas	United States
31		Arlington	Virginia	United States
32		Richmond	Virginia	United States
33		Gwangju		Korea, Republic of
34		Inchun		Korea, Republic of
35		Seoul		Korea, Republic of
36		Johor Bahru		Malaysia
37		Kota Bharu		Malaysia
38		Kuala Lumpur		Malaysia
39		Perak		Malaysia
40		Brasov		Romania
41		Bucharest		Romania
42		Craiova		Romania
43		Iasi		Romania
44		Oradea		Romania
45		Sibiu		Romania
46		Tg Mures		Romania
47		Kazan		Russian Federation
48		Lipetsk		Russian Federation
49		Moscow Russia		Russian Federation
50		Nizny Novgorod		Russian Federation
51		Samara N/A		Russian Federation
52		St Petersburg N/A		Russian Federation
53		St-Petersburg Na		Russian Federation
54		St-Petresburg		Russian Federation
55		Yaroslavl		Russian Federation
56		Beograd		Serbia
57		Kragujevac		Serbia
58		Changhua		Taiwan
59		Hua Lian		Taiwan
60		Kaohsiung		Taiwan
61		Taipei		Taiwan
62		Dnepropetrovsk		Ukraine
63		Kharkiv		Ukraine
64		Kiev		Ukraine
65		Odessa		Ukraine
66		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:

• Effectiveness and safety of 3 fixed doses (25 mg eq., 100 mg eq., and 150 mg eq.) of paliperidone palmitate in patients with schizophrenia

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00590577
• Other Study ID Numbers: CR012550; R092670PSY3007
• First Posted: Jan 10, 2008
• Last Update Posted: Jun 4, 2014
• Last Verified: May 1, 2014

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Schizophrenia; Long-acting injectable antipsychotic medication
• Additional relevant MeSH terms: Schizophrenia; Paliperidone Palmitate

Study Results

Participant Flow

Recruitment Details	The recruitment period was 8 March 2007 (first patient enrolled) to 24 March 2008 (last patient left the study). The study was performed in medical clinics located around the world.
Pre-assignment Detail	Before assignment to treatment groups, patients stopped taking disallowed medications. At the same time, patients who had not previously taken paliperidone extended release (ER) or risperidone or had previously taken it but were not currently taking another antipsychotic took paliperidone ER 6 mg/day for 4 to 6 days to assess tolerance to the drug.

Arm/Group Title	Paliperidone Palmitate 25 mg eq.	Paliperidone Palmitate 100 mg eq.	Paliperidone Palmitate 150 mg eq.	Placebo
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).
Period Title: Overall Study
STARTED	160	165	163	164
COMPLETED	83	89	90	71
NOT COMPLETED	77	76	73	93

Baseline Characteristics

Arm/Group Title	Paliperidone Palmitate 25 mg eq.	Paliperidone Palmitate 100 mg eq.	Paliperidone Palmitate 150 mg eq.	Placebo	Total
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Total of all reporting groups
Overall Participants	160	165	163	164	652
Age (Count of Participants)
<=18 years	0 0%	1 0.6%	1 0.6%	0 0%	2 0.3%
Between 18 and 65 years	160 100%	163 98.8%	160 98.2%	163 99.4%	646 99.1%
>=65 years	0 0%	1 0.6%	2 1.2%	1 0.6%	4 0.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (10.33)	38.7 (10.27)	39.4 (10.69)	39.9 (10.96)	39.3 (10.55)
Sex: Female, Male (Count of Participants)
Female	44 27.5%	55 33.3%	58 35.6%	55 33.5%	212 32.5%
Male	116 72.5%	110 66.7%	105 64.4%	109 66.5%	440 67.5%
Region of Enrollment (participants) [Number]
United States	78 48.8%	82 49.7%	85 52.1%	84 51.2%	329 50.5%
Russian Federation	32 20%	33 20%	33 20.2%	32 19.5%	130 19.9%
Ukraine	13 8.1%	14 8.5%	13 8%	13 7.9%	53 8.1%
Romania	11 6.9%	10 6.1%	8 4.9%	10 6.1%	39 6%
Taiwan	10 6.3%	10 6.1%	9 5.5%	10 6.1%	39 6%
Malaysia	7 4.4%	8 4.8%	7 4.3%	7 4.3%	29 4.4%
Korea, Republic of	7 4.4%	5 3%	6 3.7%	6 3.7%	24 3.7%
Serbia	2 1.3%	3 1.8%	2 1.2%	2 1.2%	9 1.4%

Outcome Measures

1. Primary Outcome

Title	Change in Positive and Negative Syndrome Scale (PANSS) Total Score From Baseline to Week 13 or the Last Post-baseline Assessment
Description	The 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 Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.
Time Frame	Baseline to 13 weeks or the last post-baseline assessment

Outcome Measure Data

Analysis Population Description

The primary outcome measure used the intent-to-treat analysis set, which consisted of all enrolled subjects who got at least 1 dose of paliperidone palmitate and had both a baseline and at least 1 post-baseline efficacy measurement during the study. For imputation of missing time points, last observation carried forward (LOCF) was used.

Arm/Group Title	Paliperidone Palmitate 25 mg eq.	Paliperidone Palmitate 100 mg eq.	Paliperidone Palmitate 150 mg eq.	Placebo
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).
Measure Participants	155	161	160	160
Mean (Standard Deviation) [Scores on a scale]	-8.0 (19.90)	-11.6 (17.63)	-13.2 (18.48)	-2.9 (19.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 150 mg eq., Placebo
	Comments	The overall type I error rate for testing all paliperidone palmitate doses vs. placebo for both the primary outcome and key secondary outcome was controlled at the 2-sided 0.05 significance level. The 2 families of hypotheses (in each family, comparison of each paliperidone palmitate dose vs. placebo) were tested using a parallel gatekeeping procedure that adjusts for multiplicity by using Dunnett's method in each family of hypotheses and using Bonferroni's inequality between different families.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Used analysis of covariance model with treatment (placebo, paliperidone palmitate 25, 100, 150 mg eq.) and country as factors and baseline value as a covariate. P-values adjusted for multiplicity for comparison with placebo using Dunnett's test.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	-9.8
	Confidence Interval	() 95%; -13.71 to -5.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.00
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 100 mg eq., Placebo
	Comments	The overall type I error rate for testing all paliperidone palmitate doses vs. placebo for both the primary outcome and key secondary outcome was controlled at the 2-sided 0.05 significance level. The 2 families of hypotheses (in each family, comparison of each paliperidone palmitate dose vs. placebo) were tested using a parallel gatekeeping procedure that adjusts for multiplicity by using Dunnett's method in each family of hypotheses and using Bonferroni's inequality between different families.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Used analysis of covariance model with treatment (placebo, paliperidone palmitate 25, 100, 150 mg eq.) and country as factors and baseline value as a covariate. P-values adjusted for multiplicity for comparison with placebo using Dunnett's test.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	-8.7
	Confidence Interval	() 95%; -12.62 to -4.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.00
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 25 mg eq., Placebo
	Comments	The overall type I error rate for testing all paliperidone palmitate doses vs. placebo for both the primary outcome and key secondary outcome was controlled at the 2-sided 0.05 significance level. The 2 families of hypotheses (in each family, comparison of each paliperidone palmitate dose vs. placebo) were tested using a parallel gatekeeping procedure that adjusts for multiplicity by using Dunnett's method in each family of hypotheses and using Bonferroni's inequality between different families.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	Used analysis of covariance model with treatment (placebo, paliperidone palmitate 25, 100, 150 mg eq.) and country as factors and baseline value as a covariate. P-values adjusted for multiplicity for comparison with placebo using Dunnett's test.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	-5.1
	Confidence Interval	() 95%; -9.01 to -1.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.01
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

2. Secondary Outcome

Title	Change in Personal and Social Performance Scale (PSP) Score From Baseline to Week 13 or the Last Post-baseline Assessment.
Description	The PSP scale measures the degree of normal function of a subject in interpersonal relationships and social interactions. Scores range from 1 to 100, where 1 is worst and 100 is best. The average change in PSP score for all eligible subjects was measured from the beginning of the study to Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.
Time Frame	Baseline to 13 weeks or the last post-baseline assessment

Outcome Measure Data

Analysis Population Description

The secondary outcome measures used the intent-to-treat analysis set, which consisted of all enrolled subjects who got at least 1 dose of paliperidone palmitate and had both a baseline and at least 1 post-baseline efficacy measurement during the study. For imputation of missing time points, last observation carried forward (LOCF) was used.

Arm/Group Title	Paliperidone Palmitate 25 mg eq.	Paliperidone Palmitate 100 mg eq.	Paliperidone Palmitate 150 mg eq.	Placebo
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).
Measure Participants	155	161	160	160
Mean (Standard Deviation) [Scores on a scale]	2.9 (15.29)	6.1 (13.59)	8.3 (14.69)	1.7 (15.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 150 mg eq., Placebo
	Comments	Analysis of the key secondary endpoint was conducted using an analysis of covariance model with treatment and country as factors, and the baseline PSP score as a covariate. The Dunnett-Bonferroni-based parallel gatekeeping approach was used to adjust for multiple testing.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values were adjusted for multiplicity between PANSS total score (primary efficacy endpoint) and PSP, as well as different dose levels in comparison with placebo, using the Dunnett-Bonferroni-based parallel gatekeeping method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	6.2
	Confidence Interval	() 95%; 3.26 to 9.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.49
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 100 mg eq., Placebo
	Comments	Analysis of the key secondary endpoint was conducted using an analysis of covariance model with treatment and country as factors, and the baseline PSP score as a covariate. The Dunnett-Bonferroni-based parallel gatekeeping approach was used to adjust for multiple testing.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	P-values were adjusted for multiplicity between PANSS total score (primary efficacy endpoint) and PSP, as well as different dose levels in comparison with placebo, using the Dunnett-Bonferroni-based parallel gatekeeping method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	4.4
	Confidence Interval	() 95%; 1.43 to 7.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.50
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 25 mg eq., Placebo
	Comments	Analysis of the key secondary endpoint was conducted using an analysis of covariance model with treatment and country as factors, and the baseline PSP score as a covariate. The Dunnett-Bonferroni-based parallel gatekeeping approach was used to adjust for multiple testing.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.509
	Comments	P-values were adjusted for multiplicity between PANSS total score (primary efficacy endpoint) and PSP, as well as different dose levels in comparison with placebo, using the Dunnett-Bonferroni-based parallel gatekeeping method.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	1.0
	Confidence Interval	() 95%; -1.96 to 3.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.50
	Estimation Comments	The 95% confidence intervals were unadjusted for multiplicity.

3. Secondary Outcome

Title	Change in Clinical Global Impression-Severity (CGI-S) Scores From Baseline to Week 13 or the Last Post-baseline Assessment
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. The change in CGI-S score for all eligible subjects was measured from the beginning of the study to Week 13 (i.e., the end of the double-blind treatment period) or, if the subject left the study early, from the beginning of the study to the last assessment after baseline.
Time Frame	Baseline to 13 weeks or the last post-baseline assessment

Outcome Measure Data

Analysis Population Description

The secondary outcome measures used the intent-to-treat analysis set, which consisted of all enrolled subjects who got at least 1 dose of paliperidone palmitate and had both a baseline and at least 1 post-baseline efficacy measurement during the study. For imputation of missing time points, last observation carried forward (LOCF) was used.

Arm/Group Title	Paliperidone Palmitate 25 mg eq.	Paliperidone Palmitate 100 mg eq.	Paliperidone Palmitate 150 mg eq.	Placebo
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.	Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).	Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).
Measure Participants	155	161	160	160
Median (Full Range) [Scores on a scale]	-1.0	-1.0	-1.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 150 mg eq., 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 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	Comparisons with placebo were without multiplicity adjustment.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 100 mg eq., 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 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	0.005
	Comments	Comparisons with placebo were without multiplicity adjustment.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paliperidone Palmitate 25 mg eq., 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 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	0.140
	Comments	Comparisons with placebo were without multiplicity adjustment.
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Paliperidone Palmitate 25 mg eq.		Paliperidone Palmitate 100 mg eq.		Paliperidone Palmitate 150 mg eq.		Placebo
Arm/Group Description	Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 25 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.		Paliperidone palmitate 150 mg eq. (i.m., deltoid muscle) on Day 1, and 100 mg eq. (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator) on Days 8, 36, and 64.		Paliperidone palmitate 150 mg eq. on Day 1 (i.m., deltoid muscle) and on Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).		Placebo on Day 1 (i.m., deltoid muscle) and Days 8, 36, and 64 (i.m., gluteal or deltoid muscle, left or right side, at the discretion of the investigator).
All Cause Mortality
	Paliperidone Palmitate 25 mg eq.		Paliperidone Palmitate 100 mg eq.		Paliperidone Palmitate 150 mg eq.		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
	Paliperidone Palmitate 25 mg eq.		Paliperidone Palmitate 100 mg eq.		Paliperidone Palmitate 150 mg eq.		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/ (NaN)		22/ (NaN)		13/ (NaN)		23/ (NaN)
Gastrointestinal disorders
Haemorrhoids	0/160 (0%)	0	1/165 (0.6%)	1	0/163 (0%)	0	0/164 (0%)	0
General disorders
Non-cardiac chest pain	0/160 (0%)	0	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Infections and infestations
Diverticulitis	1/160 (0.6%)	1	0/165 (0%)	0	0/163 (0%)	0	0/164 (0%)	0
Investigations
Electrocardiogram change	0/160 (0%)	0	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Nervous system disorders
Cerebrovascular accident	0/160 (0%)	0	0/165 (0%)	0	1/163 (0.6%)	1	0/164 (0%)	0
Syncope	1/160 (0.6%)	1	0/165 (0%)	0	0/163 (0%)	0	0/164 (0%)	0
Psychiatric disorders
Schizophrenia	9/160 (5.6%)	11	10/165 (6.1%)	10	5/163 (3.1%)	5	10/164 (6.1%)	10
Psychotic disorder	3/160 (1.9%)	3	7/165 (4.2%)	7	4/163 (2.5%)	4	7/164 (4.3%)	7
Suicidal ideation	3/160 (1.9%)	3	2/165 (1.2%)	2	0/163 (0%)	0	3/164 (1.8%)	3
Anxiety	0/160 (0%)	0	1/165 (0.6%)	1	1/163 (0.6%)	1	0/164 (0%)	0
Depression	1/160 (0.6%)	1	0/165 (0%)	0	1/163 (0.6%)	1	1/164 (0.6%)	1
Suicide attempt	0/160 (0%)	0	1/165 (0.6%)	1	1/163 (0.6%)	1	0/164 (0%)	0
Agitation	1/160 (0.6%)	1	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Hallucination, auditory	1/160 (0.6%)	1	0/165 (0%)	0	0/163 (0%)	0	0/164 (0%)	0
Insomnia	1/160 (0.6%)	1	0/165 (0%)	0	0/163 (0%)	0	0/164 (0%)	0
Schizoaffective disorder	0/160 (0%)	0	1/165 (0.6%)	1	0/163 (0%)	0	0/164 (0%)	0
Schizophrenia, paranoid type	0/160 (0%)	0	1/165 (0.6%)	1	0/163 (0%)	0	0/164 (0%)	0
Acute psychosis	0/160 (0%)	0	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Delusional disorder, persecutory type	0/160 (0%)	0	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Homicidal ideation	0/160 (0%)	0	0/165 (0%)	0	0/163 (0%)	0	1/164 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Paliperidone Palmitate 25 mg eq.		Paliperidone Palmitate 100 mg eq.		Paliperidone Palmitate 150 mg eq.		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/ (NaN)		27/ (NaN)		28/ (NaN)		23/ (NaN)
General disorders
Injection site pain	14/160 (8.8%)		10/165 (6.1%)		13/163 (8%)		6/164 (3.7%)
Nervous system disorders
Headache	17/160 (10.6%)		11/165 (6.7%)		10/163 (6.1%)		12/164 (7.3%)
Akathisia	2/160 (1.3%)		8/165 (4.8%)		9/163 (5.5%)		8/164 (4.9%)

Limitations/Caveats

No information on long-term (ie, more than 13-week) treatment; not designed to detect differences between doses of paliperidone palmitate; not designed to demonstrate efficacy for specific subgroups, such as subjects from a particular country

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.