A Study to Evaluate the Effectiveness and Safety of Extended-Release (ER) Paliperidone Compared With Placebo in Delaying the Recurrence of Symptoms in Bipolar I Disorder

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00490971
• Collaborator: (none)
• Enrollment: 768
• Locations: 80
• Arms: 3
• Duration (Months): 47
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness and safety of oral extended-release (ER) paliperidone compared with placebo in the prevention of the recurrence of mood symptoms in patients with Bipolar I Disorder who initially respond to treatment of an acute manic or mixed episode with paliperidone ER. Olanzapine was included as an active control arm, although the study is not designed to allow for a direct comparison of olanzapine with paliperidone.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Olanzapine; Drug: Paliperidone ER; Drug: Placebo	Phase 3

Detailed Description

This is a randomized (patients are assigned different treatments based on chance), double-blind (neither the patient nor the physician knows whether drug or placebo is being taken), active- and placebo-controlled, parallel-group, multicenter study to evaluate the efficacy (effectiveness) and safety of paliperidone ER relative to placebo in the prevention of recurrent mood symptoms associated with Bipolar I Disorder.

There are 5 phases in this study: a screening phase (lasting up to 7 days) to establish a subject's eligibility for the study,; a 3-week double-blind acute treatment phase to treat the acute or manic episode; a 12-week double-blind treatment continuation phase to establish a patient's clinical stability,; a double-blind treatment maintenance phase to measure the time to symptom recurrence that will last until the patient experiences a recurrence,; and a follow-up phase consisting of a visit approximately 1 week after the last study visit. All antipsychotic drugs and all mood stabilizers other than study drug must be discontinued before the first study drug administration.

Hospitalization is required for at least the first 7 days of the acute treatment phase. At the beginning of the acute treatment phase, patients will be randomly assigned to receive ER paliperidone or olanzapine in a 4:1 ratio. Patients in the ER paliperidone group who have a clinical response at the end of the acute treatment phase, remain clinically stable throughout the continuation phase, and achieve remission for each of the last 3 weeks of the continuation phase will again be randomly assigned: they will be assigned in a 1:1 ratio to receive ER paliperidone or placebo in the maintenance phase. Patients in the olanzapine treatment group who fulfill the same criteria will continue receiving double-blind treatment with olanzapine in the maintenance phase.

Measures of efficacy used are the Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression - Bipolar Disorder - Severity of Illness Scale (CGI-BP-S), Global Assessment of Functioning (GAF), the Short Form-36 to measure health-related functional status, and the sleep visual analog scale (VAS).

Safety evaluations include monitoring of adverse events, clinical laboratory tests (including urine pregnancy testing and hemoglobin A1c), 12-lead ECG, vital signs measurements, measurement of orthostatic changes in pulse and blood pressure, physical examinations (including height, body weight, and waist circumference), and monitoring of extrapyramidal symptoms using the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), and the Simpson Angus Scale (SAS). In addition, the Scale for Suicidal Ideation will be administered to assess suicidality.

The primary hypothesis for this study is that, during the long-term treatment of patients with Bipolar I Disorder who maintain clinical stability after an acute manic or mixed episode, ER paliperidone is superior to placebo in delaying the time to recurrence of any mood symptoms associated with Bipolar I Disorder. Patients begin the acute treatment phase at 6.0 mg/day of oral ER paliperidone or 10 mg/day of oral olanzapine. Dosages may be adjusted, as needed, between 3 to 12 mg/day of ER paliperidone or 5 to 20 mg/day of olanzapine, through the end of the continuation phase. Then, in the maintenance phase, patients receive the dosage of ER paliperidone (or ER paliperidone placebo) or olanzapine reached at the end of the continuation phase. They remain on those dosages until the end of the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 768 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Active- and Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Extended-Release Paliperidone as Maintenance Treatment After an Acute Manic or Mixed Episode Associated With Bipolar I Disorder
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Paliperidone ER	Drug: Paliperidone ER; Once daily in dose range of 3 to 12 mg/day for 15 weeks, then until recurrence
Placebo Comparator: Placebo	Drug: Placebo; Once daily until recurrence (only after initial 15 weeks on paliperidone ER)
Active Comparator: Olanzapine	Drug: Olanzapine; Once daily in dose range of 5 to 20 mg/day for 15 weeks, then until recurrence

Outcome Measures

Primary Outcome Measures

1. Time to Recurrence of Any Mood Symptoms (Manic or Depressive) Associated With Bipolar I Disorder [Date of randomization into the maintenance phase until the first occurrence of recurrence of any symptoms or discontinuation from the study, assessed over a period of 41 months.]

   Time to first recurrence of any mood symptoms (ie, manic or depressive) associated with bipolar I disorder during the maintenance phase, after maintaining clinical stability during continued treatment with paliperidone ER over a period of 15 weeks. The time period was from occurrence of acute manic or mixed episode to Week 15. This outcome was measured using combination of various scales, hospitalization for any mood symptoms, use of any medicines for an mood episode and clinical events suggestive of recurrent mood episode associated with bipolar I disorder.

Secondary Outcome Measures

1. Time to Recurrence of Manic Symptoms Associated With Bipolar I Disorder [Date of randomization into the maintenance phase until the first occurrence of recurrence of manic symptoms or discontinuation from the study, assessed over a period of 41 months.]

   This was the key secondary efficacy end-point. Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of manic symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.

2. Time to Recurrence of Depressive Symptoms Associated With Bipolar I Disorder [Date of randomization into the maintenance phase until the first occurrence of recurrence of depressive symptoms or discontinuation from the study, assessed over a period of 41 months.]

   Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of depressive symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.

Other Outcome Measures

1. Young Mania Rating Scale (YMRS): Change From Baseline [From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).]

   This is method by which condition of patient suffering with mania is checked. In this scale patient's condition is assessed using 11 items. A severity rating is assigned to each of 11 items based on the how subject feels of his or her condition and the physicians observation of patients behavior. The range of the scale is 0 to 60. A higher score indicates a more severe condition. Change from baseline (Day 105) in the double-blind maintenance phase to the last postbaseline assessment.

2. Montgomery-Asberg Depression Rating Scale (MADRS) [From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).]

   The MADRS consists of 10 items covering all the important complaints which patient with depression have (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Item is scored from 0 (normal) to 6 (severe). Total score (0 to 60) is calculated by adding the scores of all 10 items. A higher score represents a more severe condition. Negative Change in Score Indicates Improvement.

3. Global Assessment of Functioning (GAF): Change From Baseline [From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).]

   This scale is used when the clinical progress of a subject needs to be assessed in global terms, using a single measure. The GAF scale is rated with respect to psychological, social, and occupational functioning at the time of the assessment only. A higher score indicates a better functioning, with an overall range from 1 to 100. Positive Change in Score Indicates Improvement.

4. Clinical Global Impression - Bipolar Disorder - Severity of Illness (CGI-BP-S): Change From Baseline [From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).]

   The CGI-BP-S rating scale is used to rate the severity of bipolar disorder, including both depressed and manic components, on a 7-point scale ranging from 1 (not ill) to 7 (very severely ill). This scale permits a global evaluation of the subject's bipolar condition at a given time. Negative Change in Score Indicates Improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Meet DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for Bipolar I Disorder Most Recent Episode Manic or Mixed (with or without psychotic features)

• have a history of at least 2 previously documented mood episodes associated with Bipolar I Disorder (1 of which must be a manic or mixed episode) that required medical treatment within the past 3 years

• a total score of at least 20 on the YMRS at screening and at Day 1 of the study.

Exclusion Criteria:

• Meet DSM-IV criteria for any type of episode associated with bipolar disorder other than Bipolar I Disorder Most Recent Episode Manic or Mixed

• Meet DSM-IV criteria for rapid cycling

• Meet DSM-IV criteria for schizoaffective disorder

• Known or suspected borderline or antisocial personality disorder

• be, in the opinion of the investigator, at significant immediate risk for suicidal or violent behavior during the course of the study based on current status or prior history (e.g., suicide attempts during previous episodes).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Scottsdale	Arizona	United States
2		Riverside	California	United States
3		San Diego	California	United States
4		Jacksonville	Florida	United States
5		Honolulu	Hawaii	United States
6		Chicago	Illinois	United States
7		Hoffman Estates	Illinois	United States
8		Wichita	Kansas	United States
9		New Orleans	Louisiana	United States
10		Willingboro	New Jersey	United States
11		Cincinnati	Ohio	United States
12		Lyndhurst	Ohio	United States
13		Philadelphia	Pennsylvania	United States
14		Arlington	Texas	United States
15		Austin	Texas	United States
16		Bellevue	Washington	United States
17		Bulgaria		Bulgaria
18		Radnevo N/A		Bulgaria
19		Sofia		Bulgaria
20		Baoding		China
21		Beijing		China
22		Guangzhou		China
23		Nanjing		China
24		Shanghai		China
25		Suzhou		China
26		Xi'An		China
27		San Jose		Costa Rica
28		San José		Costa Rica
29		Casablanca		France
30		Manouba		France
31		Berlin		Germany
32		Bochum		Germany
33		Chemnitz		Germany
34		Düsseldorf		Germany
35		Göttingen		Germany
36		Jena		Germany
37		Lübeck		Germany
38		Bangalore		India
39		Calicut		India
40		Coimbatore		India
41		Hyderabad		India
42		Ludhiana		India
43		Pune		India
44		Varanasi		India
45		Kuala Lumpur		Malaysia
46		Panama Panama		Panama
47		Panama		Panama
48		Gdansk N/A		Poland
49		Krakow N/A		Poland
50		Leszno N/A		Poland
51		Skape		Poland
52		Swiecie Poland		Poland
53		Torun N/A		Poland
54		Tuszyn N/A		Poland
55		Bucharest		Romania
56		Craiova		Romania
57		Iasi		Romania
58		Tg Mures		Romania
59		Timisoara		Romania
60		Krasnodar N/A		Russian Federation
61		Nizny Novgorod		Russian Federation
62		Perm		Russian Federation
63		Smolensk Region N/A		Russian Federation
64		Yaroslavl N/A		Russian Federation
65		Belgrade		Serbia
66		Beograd		Serbia
67		Gornja Toponica		Serbia
68		Kragujevac		Serbia
69		Novi Knezevac		Serbia
70		Cape Town		South Africa
71		Durban Kn		South Africa
72		Johannesburg		South Africa
73		Pretoria		South Africa
74		Ankara		Turkey
75		Manisa		Turkey
76		Dnepropetrovsk		Ukraine
77		Donetsk		Ukraine
78		Kiev		Ukraine
79		Lvov		Ukraine
80		Vinnitsa		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

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00490971
• Other Study ID Numbers: CR010825; R076477BIM3004
• First Posted: Jun 25, 2007
• Last Update Posted: Apr 15, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Bipolar Disorder; Mania; Depression; Manic-Depressive Disorder
• Additional relevant MeSH terms: Disease; Bipolar Disorder; Olanzapine; Paliperidone Palmitate

Study Results

Participant Flow

Pre-assignment Detail	The double-blind (ie, niether physician nor patient knows the treatment that the patient receives) study has 15-week acute/continuation phase followed by variable-duration maintenance phase (lasting until patient had recurrence or discontinued treatment) to assess effect of paliperidone on maintenance of remission of Bipolar I Disorder

Arm/Group Title	Paliperidone Extented Release (ER)	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Period Title: Acute/Continuation
STARTED	614	148	0	0	0
COMPLETED	308	86	0	0	0
NOT COMPLETED	306	62	0	0	0
Period Title: Acute/Continuation
STARTED	0	0	147	149	83
COMPLETED	0	0	96	96	44
NOT COMPLETED	0	0	51	53	39

Baseline Characteristics

Arm/Group Title	Paliperidone ER	Olanzapine	Total
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Total of all reporting groups
Overall Participants	614	148	762
Age (Count of Participants)
<=18 years	7 1.1%	3 2%	10 1.3%
Between 18 and 65 years	606 98.7%	145 98%	751 98.6%
>=65 years	1 0.2%	0 0%	1 0.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.7 (11.93)	39.2 (11.49)	39.6 (11.84)
Sex: Female, Male (Count of Participants)
Female	310 50.5%	80 54.1%	390 51.2%
Male	304 49.5%	68 45.9%	372 48.8%
Region of Enrollment (participants) [Number]
Asia	162 26.4%	36 24.3%	198 26%
Eastern Europe	129 21%	31 20.9%	160 21%
European Union	71 11.6%	19 12.8%	90 11.8%
North America	177 28.8%	41 27.7%	218 28.6%
Other	75 12.2%	21 14.2%	96 12.6%
India	69 11.2%	14 9.5%	83 10.9%
Malaysia	7 1.1%	2 1.4%	9 1.2%
China	86 14%	20 13.5%	106 13.9%
Russian Federation	51 8.3%	11 7.4%	62 8.1%
Serbia	32 5.2%	8 5.4%	40 5.2%
Ukraine	46 7.5%	12 8.1%	58 7.6%
Bulgaria	27 4.4%	6 4.1%	33 4.3%
Germany	6 1%	3 2%	9 1.2%
Poland	16 2.6%	5 3.4%	21 2.8%
Romania	22 3.6%	5 3.4%	27 3.5%
Costa Rica	12 2%	4 2.7%	16 2.1%
Morocco	6 1%	2 1.4%	8 1%
Panama	3 0.5%	1 0.7%	4 0.5%
South Africa	26 4.2%	6 4.1%	32 4.2%
Tunisia	10 1.6%	4 2.7%	14 1.8%
Turkey	18 2.9%	4 2.7%	22 2.9%
United States	177 28.8%	41 27.7%	218 28.6%
AgeCategorical (participants) [Number]
18-25	98 16%	25 16.9%	123 16.1%
26-50	378 61.6%	96 64.9%	474 62.2%
51-65	138 22.5%	27 18.2%	165 21.7%
>65	0 0%	0 0%	0 0%
<18	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Time to Recurrence of Any Mood Symptoms (Manic or Depressive) Associated With Bipolar I Disorder
Description	Time to first recurrence of any mood symptoms (ie, manic or depressive) associated with bipolar I disorder during the maintenance phase, after maintaining clinical stability during continued treatment with paliperidone ER over a period of 15 weeks. The time period was from occurrence of acute manic or mixed episode to Week 15. This outcome was measured using combination of various scales, hospitalization for any mood symptoms, use of any medicines for an mood episode and clinical events suggestive of recurrent mood episode associated with bipolar I disorder.
Time Frame	Date of randomization into the maintenance phase until the first occurrence of recurrence of any symptoms or discontinuation from the study, assessed over a period of 41 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set (ITT) in maintenance (MA) phase, which included participants who entered the MA phase and took at least 1 dose of study medication.

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	0	0	144	146	82
25% Quantile of Time to Recurrence	85.0	140.0	541
Median Time to Recurrence	283.0	558.0	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo
	Comments	Null hypothesis: there is no difference between Pali/Pali and Pali/Placebo in the time to recurrence of any mood symptoms related to bipolar I disorder. An interim analysis was performed when approximately 85% of the required number of recurrences were reported in Pali/Pali and Pali/Placebo treatment groups. A flexible group-sequential approach was adopted. The general family of alpha spending function based on the rho-family with rho=2.5 at overall type I error of 0.025 (1-sided) was employed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	The two treatment groups were compared using a weighted z-statistic based on rho-family of alpha spending function at information fraction of 85.0% at interim analysis analysis (rho=2.5) at 0.025 (1-sided) level. One-sided alpha at final was 0.0195.
	Method	Weighted Z- test
	Comments

2. Secondary Outcome

Title	Time to Recurrence of Manic Symptoms Associated With Bipolar I Disorder
Description	This was the key secondary efficacy end-point. Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of manic symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.
Time Frame	Date of randomization into the maintenance phase until the first occurrence of recurrence of manic symptoms or discontinuation from the study, assessed over a period of 41 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set in MA phase, which included participants who entered the MA phase and took at least 1 dose of study medication.

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	0	0	144	146	82
25% Quantile of Time to Recurrence	194.0	498.0	NA
Median Time to Recurrence	550.0	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo
	Comments	At the time of interim analysis of the primary efficacy endpoint, the proportion of recurrence of manic symptoms was 81.9% of the number of recurrence of manic symptoms at final analysis. A flexible group-sequential approach was adopted. The general family of alpha spending function based on the rho-family with rho=2.5 at overall type I error of 0.025 (1-sided) was employed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The two treatment groups were compared using a weighted z-statistic based on rho-family of alpha spending function at information fraction of 81.9% at interim analysis analysis (rho=2.5) at 0.025 (1-sided) level. One-sided alpha at final was 0.0198.
	Method	Weighted z-test
	Comments

3. Secondary Outcome

Title	Time to Recurrence of Depressive Symptoms Associated With Bipolar I Disorder
Description	Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of depressive symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.
Time Frame	Date of randomization into the maintenance phase until the first occurrence of recurrence of depressive symptoms or discontinuation from the study, assessed over a period of 41 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set in MA period, which included participants who entered the maintenance phase and took at least 1 dose of study medication.

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	0	0	144	146	82
Number (95% Confidence Interval) [Days]	503.0	448.0	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo, Pali/Pali
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated with Pali/Placebo in the numerator and Pali/Pali in the denominator

4. Other Pre-specified Outcome

Title	Young Mania Rating Scale (YMRS): Change From Baseline
Description	This is method by which condition of patient suffering with mania is checked. In this scale patient's condition is assessed using 11 items. A severity rating is assigned to each of 11 items based on the how subject feels of his or her condition and the physicians observation of patients behavior. The range of the scale is 0 to 60. A higher score indicates a more severe condition. Change from baseline (Day 105) in the double-blind maintenance phase to the last postbaseline assessment.
Time Frame	From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	602	145	143	144	81
Mean (Standard Deviation) [Scores on the scale]	-19.2 (11.23)	-19.3 (10.25)	9.0 (11.78)	4.2 (9.33)	1.3 (6.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo, Pali/Pali
	Comments	Change from Baseline (Maintenance Phase) to Endpoint (Maintenance Phase)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment group (Pali/Pali, Pali/Placebo) and country as factors with baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -6.92 to -1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	The MADRS consists of 10 items covering all the important complaints which patient with depression have (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Item is scored from 0 (normal) to 6 (severe). Total score (0 to 60) is calculated by adding the scores of all 10 items. A higher score represents a more severe condition. Negative Change in Score Indicates Improvement.
Time Frame	From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	597	144	143	144	81
Mean (Standard Deviation) [Scores on the scale]	-2.7 (8.21)	-2.7 (7.82)	6.0 (9.16)	6.1 (10.10)	2.5 (7.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo, Pali/Pali
	Comments	Change from Baseline (Maintenance Phase) to Endpoint (Maintenance Phase)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.763
	Comments
	Method	ANCOVA
	Comments	ANCOVA Model with treatment (Pali/Pali, Pali/Placebo) and country as factors with baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -1.87 to 2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Global Assessment of Functioning (GAF): Change From Baseline
Description	This scale is used when the clinical progress of a subject needs to be assessed in global terms, using a single measure. The GAF scale is rated with respect to psychological, social, and occupational functioning at the time of the assessment only. A higher score indicates a better functioning, with an overall range from 1 to 100. Positive Change in Score Indicates Improvement.
Time Frame	From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	575	137	131	135	77
Mean (Standard Deviation) [Scores on the scale]	19.6 (17.38)	20.8 (18.26)	-15.2 (20.93)	-8.9 (17.75)	-4.2 (13.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo, Pali/Pali
	Comments	Change from Baseline (Maintenance Phase) to Endpoint (Maintenance Phase)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments	ANCOVA Model with treatment (Pali/Pali, Pali/Placebo) and country as factors with baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.7
	Confidence Interval	(2-Sided) 95%; 1.40 to 10.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Clinical Global Impression - Bipolar Disorder - Severity of Illness (CGI-BP-S): Change From Baseline
Description	The CGI-BP-S rating scale is used to rate the severity of bipolar disorder, including both depressed and manic components, on a 7-point scale ranging from 1 (not ill) to 7 (very severely ill). This scale permits a global evaluation of the subject's bipolar condition at a given time. Negative Change in Score Indicates Improvement.
Time Frame	From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization).

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Paliperidone ER	Olanzapine	Pali/Placebo	Pali/Pali	Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.	Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.	Maintenance period. Placebo (Paliperidone in the acute and continuation period).	Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)	Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
Measure Participants	601	145	143	144	81
Median (Full Range) [Scores on the scale]	-2	-3	2	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pali/Placebo, Pali/Pali
	Comments	Change from Baseline (Maintenance Phase) to Endpoint (Maintenance Phase)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANCOVA
	Comments	ANCOVA Model on ranks with treatment (Pali/Pali, Pali/Placebo) and country as factors with baseline value as covariate

Adverse Events

Arm/Group Title	Paliperidone ER		Olanzapine		Pali/Placebo		Pali/Pali		Olan/Olan
Arm/Group Description	Acute and continuation period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily.		Acute and continuation period. Olanzapine: Oral tablet, 5 mg/day to 20 mg/day, Once daily.		Maintenance period. Placebo (Paliperidone in the acute and continuation period).		Maintenance period. Paliperidone ER: Oral tablet, 3 mg/day to 12 mg/day, Once daily (Paliperidone in the acute and continuation period)		Maintenance period. Olanzapine Oral tablet, 5 mg/day to 20 mg/day, Once daily (Olanzapine in the acute and continuation period)
All Cause Mortality
	Paliperidone ER		Olanzapine		Pali/Placebo		Pali/Pali		Olan/Olan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Paliperidone ER		Olanzapine		Pali/Placebo		Pali/Pali		Olan/Olan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/614 (6.8%)		10/148 (6.8%)		33/147 (22.4%)		16/149 (10.7%)		8/83 (9.6%)
Cardiac disorders
Myocardial infarction	2/614 (0.3%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Eye disorders
Vision blurred	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Gastrointestinal disorders
Gastritis	0/614 (0%)		1/148 (0.7%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Pancreatitis	0/614 (0%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		1/83 (1.2%)
General disorders
Death	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Infections and infestations
Abdominal infection	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Hepatitis viral	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Pneumonia	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Sinusitis	0/614 (0%)		1/148 (0.7%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Injury, poisoning and procedural complications
Chest injury	0/614 (0%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		1/83 (1.2%)
Head injury	0/614 (0%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		1/83 (1.2%)
Multiple fractures	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Post procedural complication	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Investigations
Blood potassium decreased	0/614 (0%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		1/83 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer stage III	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Nervous system disorders
Akathisia	2/614 (0.3%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Extrapyramidal disorder	2/614 (0.3%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Hypoxic encephalopathy	0/614 (0%)		0/148 (0%)		1/147 (0.7%)		0/149 (0%)		0/83 (0%)
Neuroleptic malignant syndrome	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Psychomotor hyperactivity	2/614 (0.3%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Psychiatric disorders
Agitation	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Alcohol abuse	2/614 (0.3%)		1/148 (0.7%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Anger	0/614 (0%)		0/148 (0%)		1/147 (0.7%)		0/149 (0%)		0/83 (0%)
Anxiety	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Bipolar I disorder	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Catatonia	0/614 (0%)		1/148 (0.7%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Completed suicide	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Depression	4/614 (0.7%)		1/148 (0.7%)		8/147 (5.4%)		4/149 (2.7%)		1/83 (1.2%)
Depressive symptom	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Hypomania	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Insomnia	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Major depression	0/614 (0%)		0/148 (0%)		1/147 (0.7%)		1/149 (0.7%)		0/83 (0%)
Mania	10/614 (1.6%)		6/148 (4.1%)		22/147 (15%)		3/149 (2%)		4/83 (4.8%)
Pressure of speech	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Psychotic disorder	0/614 (0%)		1/148 (0.7%)		1/147 (0.7%)		0/149 (0%)		0/83 (0%)
Self-injurious ideation	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Suicidal behaviour	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Suicidal ideation	6/614 (1%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Suicide attempt	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Tachyphrenia	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Skin and subcutaneous tissue disorders
Leukoplakia	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Surgical and medical procedures
Breast operation	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Mastectomy	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Nasal operation	0/614 (0%)		0/148 (0%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Sinus operation	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Vascular disorders
Hypertension	2/614 (0.3%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Orthostatic hypotension	1/614 (0.2%)		0/148 (0%)		0/147 (0%)		0/149 (0%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	Paliperidone ER		Olanzapine		Pali/Placebo		Pali/Pali		Olan/Olan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	351/614 (57.2%)		79/148 (53.4%)		38/147 (25.9%)		38/149 (25.5%)		26/83 (31.3%)
Gastrointestinal disorders
Dry mouth	28/614 (4.6%)		14/148 (9.5%)		2/147 (1.4%)		1/149 (0.7%)		1/83 (1.2%)
Nausea	33/614 (5.4%)		2/148 (1.4%)		2/147 (1.4%)		1/149 (0.7%)		0/83 (0%)
Investigations
Weight decreased	7/614 (1.1%)		0/148 (0%)		9/147 (6.1%)		4/149 (2.7%)		1/83 (1.2%)
Weight increased	51/614 (8.3%)		18/148 (12.2%)		10/147 (6.8%)		12/149 (8.1%)		7/83 (8.4%)
Metabolism and nutrition disorders
Increased appetite	23/614 (3.7%)		13/148 (8.8%)		0/147 (0%)		1/149 (0.7%)		0/83 (0%)
Nervous system disorders
Akathisia	83/614 (13.5%)		11/148 (7.4%)		1/147 (0.7%)		1/149 (0.7%)		2/83 (2.4%)
Dizziness	41/614 (6.7%)		4/148 (2.7%)		1/147 (0.7%)		4/149 (2.7%)		0/83 (0%)
Extrapyramidal disorder	54/614 (8.8%)		4/148 (2.7%)		1/147 (0.7%)		2/149 (1.3%)		1/83 (1.2%)
Headache	78/614 (12.7%)		14/148 (9.5%)		7/147 (4.8%)		4/149 (2.7%)		7/83 (8.4%)
Sedation	38/614 (6.2%)		25/148 (16.9%)		0/147 (0%)		0/149 (0%)		2/83 (2.4%)
Somnolence	76/614 (12.4%)		23/148 (15.5%)		0/147 (0%)		5/149 (3.4%)		1/83 (1.2%)
Tremor	34/614 (5.5%)		4/148 (2.7%)		0/147 (0%)		1/149 (0.7%)		3/83 (3.6%)
Psychiatric disorders
Insomnia	83/614 (13.5%)		15/148 (10.1%)		14/147 (9.5%)		13/149 (8.7%)		7/83 (8.4%)

Limitations/Caveats

The study employed a randomized withdrawal design, and as such, was enriched for responders to the study drug. Thus, the long-term efficacy demonstrated cannot be extrapolated to a population of patients without prior exposure to paliperidone ER.

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.