A Study of Relapse Prevention and the Effectiveness of Long-acting Injectable Risperidone and Quetiapine Tablets in the Treatment of Patients With Schizophrenia or Schizoaffective Disorder

• Sponsor: Janssen-Cilag International NV (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00216476
• Collaborator: (none)
• Enrollment: 753
• Locations: 98
• Arms: 3
• Duration (Months): 37
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate whether a long-acting injectable formulation of risperidone provides better effectiveness over 2 years, as measured by the time to relapse, compared with quetiapine tablets in a routine psychiatric care setting. Aripiprazole will be investigated in a descriptive manner.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Psychotic Disorders	Drug: Aripiprazole; Drug: Risperidone Long Acting Injectable (LAI); Drug: Quetiapine	Phase 3

Detailed Description

Although many schizophrenia patients currently take oral antipsychotic medications, it is estimated that up to 75% of them have difficulty adhering to the daily oral regimen. Long-acting injectable formulations may eliminate the need for daily medication and enhance patient compliance with the treatment regimen. This is an open-label (all people involved know the identity of the intervention), randomized (study drug assigned by chance) study of a formulation of risperidone (coated microspheres) injected into the muscle at 2 week intervals over 104 weeks in stable patients with schizophrenia or schizoaffective disorder, who are being treated with oral risperidone, olanzapine, or other conventional antipsychotic agents. A comparator group will receive tablets of quetiapine to be taken 2 or 3 times daily, depending on the optimal dosage. In countries where aripiprazole is available, aripiprazole was also included in a descriptive manner. Reasons for switching symptomatically stable patients from their current antipsychotic treatment include insufficient effectiveness of the medication on symptoms, adverse events, or a patient's request. The principal measure of effectiveness of the drug is the time to relapse. Assessments of effectiveness also include: Positive and Negative Syndrome Scale (PANSS), which measures the symptoms of schizophrenia; overall severity of illness measured by the Clinical Global Impression subscale (CGI-S); patient's condition measured by the Clinical Global Impression condition subscale (CGI-C); quality of life assessed by the SF-12 survey. Safety evaluations include incidence of adverse events, Extrapyramidal Symptoms Rating Scale (ESRS), clinical laboratory tests (biochemistry, haematology, and urinalysis), and vital signs (pulse, blood pressure). The study hypothesis is that treatment with long-acting risperidone injected intramuscularly every 2 weeks provides better effectiveness than quetiapine, as measured by time to relapse, in patients with schizophrenia or schizoaffective disorder. Risperidone injections 25mg biweekly for 104 weeks, increasing or decreasing (increments of 12.5mg) at investigator's discretion. Risperidone tablets (2mg daily for 2 days) for patients starting on risperidone. Quetiapine and Aripiprazole used according to package insert.

Study Design

• Study Type: Interventional
• Actual Enrollment: 753 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CONSTATRE: Risperdal Consta Trial Of Relapse Prevention And Effectiveness
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Nov 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Risperidone Long Acting Injectable (LAI) 25 mg injection every 2 weeks until week 104. Dosage may be increased or decreased in steps of 12.5 mg. Additional oral risperidone can be administered as required until a dose increase becomes effective.	Drug: Risperidone Long Acting Injectable (LAI); 25 mg injection every 2 weeks until week 104. Dosage may be increased or decreased in steps of 12.5 mg. Additional oral risperidone can be administered as required until a dose increase becomes effective.
Active Comparator: 002 Quetiapine Oral tablets are titrated from 50 mg daily to 300-400 mg daily in first 4 days. Subsequently treatment is maintained for 104 weeks and dosage can be adjusted with increments or decrements of 25 to 50 mg.	Drug: Quetiapine; Oral tablets are titrated from 50 mg daily to 300-400 mg daily in first 4 days. Subsequently treatment is maintained for 104 weeks and dosage can be adjusted with increments or decrements of 25 to 50 mg.
Other: 003 Aripiprazole 10-30 mg oral once daily for 104 weeks	Drug: Aripiprazole; 10-30 mg oral once daily for 104 weeks

Outcome Measures

Primary Outcome Measures

1. Mean Relapse Free Period(Risperidone LAI Versus Quetiapine) [Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)]

   Relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. The relapse rate in each treatment arm was estimated using the Kaplan-Meier method.

Secondary Outcome Measures

1. Mean Relapse Free Period (Exploratory/Aripiprazole) [Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)]

   As for risperidone and quetiapine, relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. Since aripiprazole was new on the market at the time the study was conducted, this aripiprazole analysis was exploratory.

2. Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score [Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)]

   The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item PANSS scale. The PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, i.e., the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items). Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme).

3. Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score [Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Month 24 or earlier)]

   The 7-point CGI scale of Severity (CGI-S) was used to assess the severity of a subject's psychotic condition (0= normal, not at all ill, 1= borderline, etc. and 6= among the most extremely ill subjects).

4. Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores [Assessed at the moment the subject was randomized to a treatment arm (baseline visit) and after 1, 3, 6, 12, 18, and 24 months of treatment]

   Quality of life was assessed by means of the 12-item SF-12® survey. Two parameters, i.e., PCS (physical component summary) and MCS (mental component summary) were calculated. Both components scores range from 0 to 100 with higher scores indicating better QOL.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Diseases, 4th edition (DSM-IV)

• Patients currently treated with oral risperidone, olanzapine or a conventional neuroleptic monotherapy at doses not exceeding 6 mg risperdal, 20 mg olanzapine, or a conversion dose of 10 mg haloperidol for oral conventional agents

• Patients who are stable (judged clinically stable by the investigator and on a stable dose of medication for 4 weeks or longer) but not optimally treated (non-satisfactory treatment regarding symptoms or adverse events)

Exclusion Criteria:

• Diagnosis other than schizophrenia or schizoaffective disorder by DSM-IV Axis I criteria

• Patients being treated with antipsychotic agents other than oral risperidone, olanzapine or conventional oral neuroleptic agents

• Patients with known hypersensitivity to oral risperidone, quetiapine, aripiprazole, or who are known non-responders to oral risperidone, quetiapine, aripiprazole or to previous treatment with at least 2 antipsychotic agents

• Patients treated with mood stabilizers or antidepressants who are not on stable dose for at least 3 months before study initiation

• Pregnant or nursing females, or those lacking adequate contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Hall In Tirol		Austria
2		Linz		Austria
3		Neunkirchen		Austria
4		Pleven		Bulgaria
5		Sofia Sofia		Bulgaria
6		Sofia		Bulgaria
7		Osijek		Croatia
8		Rijeka		Croatia
9		Split		Croatia
10		Zagreb		Croatia
11		Brno		Czech Republic
12		Lnare		Czech Republic
13		Opava N/A		Czech Republic
14		Pardubice		Czech Republic
15		Plzen Czechia		Czech Republic
16		Praha 2 N/A		Czech Republic
17		Praha 8		Czech Republic
18		Uhersky Brod		Czech Republic
19		Usti Nad Labem N/A		Czech Republic
20		Middelfart N/A		Denmark
21		Vordingborg N/A		Denmark
22		Pÿrnu N/A		Estonia
23		Tallinn N/A		Estonia
24		Tartu N/A		Estonia
25		Bron N/A		France
26		Brumath Cedex		France
27		Creteil		France
28		Dieppe N/A		France
29		Henin Beaumont		France
30		Mont St Martin		France
31		Poitiers N/A		France
32		Reims		France
33		Roubaix		France
34		Toulouse N/A		France
35		Augsburg		Germany
36		Berlin		Germany
37		Bochum		Germany
38		Duisburg		Germany
39		Düsseldorf		Germany
40		Karlstadt		Germany
41		Krefeld		Germany
42		München		Germany
43		Oranienburg		Germany
44		Stralsund		Germany
45		Heraklion -Crete		Greece
46		Thessalonikis		Greece
47		Budapest N/A		Hungary
48		Budapest		Hungary
49		Gyula		Hungary
50		Gyõr		Hungary
51		Kistarcsa		Hungary
52		Szeged N/A		Hungary
53		Vac N/A		Hungary
54		Cork		Ireland
55		Dublin N/A		Ireland
56		Kerry		Ireland
57		Sligo N/A		Ireland
58		Jerusalem		Israel
59		Ramat-Gan		Israel
60		Tel Aviv		Israel
61		Jelgava		Latvia
62		Riga		Latvia
63		Alytus		Lithuania
64		Kaunas		Lithuania
65		Klaipeda		Lithuania
66		Siauliai		Lithuania
67		Vilnius		Lithuania
68		Choroszcz		Poland
69		Gdynia Na		Poland
70		Poznan		Poland
71		Warszawa		Poland
72		Coimbra		Portugal
73		Porto N/A		Portugal
74		Bucharest		Romania
75		Bucuresti		Romania
76		Craiova		Romania
77		Iasi		Romania
78		Al Khobar		Saudi Arabia
79		Kosice		Slovakia
80		Zvolen		Slovakia
81		Begunje		Slovenia
82		Ljubljana		Slovenia
83		Ormoz		Slovenia
84		Madrid		Spain
85		Oviedo (Asturias)		Spain
86		Sevilla N/A		Spain
87		Valencia N/A		Spain
88		Göteborg		Sweden
89		Trollhättan		Sweden
90		Ankara Turkey		Turkey
91		Bakirkoy/Istanbul N/A		Turkey
92		Istanbul		Turkey
93		Izmir		Turkey
94		Barnet		United Kingdom
95		Barnsley		United Kingdom
96		Hull		United Kingdom
97		Llantrissant		United Kingdom
98		Swansea		United Kingdom

Sponsors and Collaborators

• Janssen-Cilag International NV

Investigators

• Study Director: Janssen-Cilag International NV Clinical Trial, Janssen-Cilag International NV

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CONSTATRE: Risperdal� Consta� Trial of Relapse Prevention and Effectiveness RIS-SCH-3001 Study Results Synopsis

Publications

None provided.

• Responsible Party: Janssen-Cilag International NV
• ClinicalTrials.gov Identifier: NCT00216476
• Other Study ID Numbers: CR002269
• First Posted: Sep 22, 2005
• Last Update Posted: Apr 16, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Janssen-Cilag International NV: Schizophrenia, relapse prevention; Antipsychotic agents; Long-acting risperidone; Quetiapine; Aripiprazole
• Additional relevant MeSH terms: Recurrence; Schizophrenia; Mental Disorders; Psychotic Disorders; Risperidone; Quetiapine Fumarate; Aripiprazole

Study Results

Participant Flow

Recruitment Details	Subjects had a diagnosis of schizophrenia or schizoaffective disorder (according to the Diagnostic and Statistical Manual of Mental Disorders - 4th edition [DSM-IV]) and were treated with oral risperidone, olanzapine, or conventional oral neuroleptic monotherapy at screening. They were to be symptomatically stable but not optimally treated.

Arm/Group Title	Risperidone LAI	Quetiapine	Aripiprazole
Arm/Group Description	Risperidone Long Acting Injectable (LAI) intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral Quetiapine, target dose of 300-400 mg twice daily (b.i.d.) or three times daily (t.i.d.)	oral Aripiprazole, recommended maintenance dose of 10-30 mg once daily (q.d.)
Period Title: Overall Study
STARTED	329	337	45
COMPLETED	224	230	28
NOT COMPLETED	105	107	17

Baseline Characteristics

Arm/Group Title	Risperidone LAI	Quetiapine	Total
Arm/Group Description	intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral, target dose of 300-400 mg b.i.d. or t.i.d.	Total of all reporting groups
Overall Participants	329	337	666
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (12.48)	42.6 (13.14)	41.6 (12.85)
Sex: Female, Male (Count of Participants)
Female	134 40.7%	146 43.3%	280 42%
Male	195 59.3%	191 56.7%	386 58%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	320 97.3%	330 97.9%	650 97.6%
Oriental	1 0.3%	2 0.6%	3 0.5%
Hispanic	2 0.6%	0 0%	2 0.3%
Black	1 0.3%	0 0%	1 0.2%
Arab	5 1.5%	4 1.2%	9 1.4%
Pakistani	0 0%	1 0.3%	1 0.2%
Body Mass Index (BMI) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	27.6 (5.23)	27.0 (5.32)	27.3 (5.28)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	80.4 (16.93)	79.0 (17.75)	79.7 (17.35)

Outcome Measures

1. Primary Outcome

Title	Mean Relapse Free Period(Risperidone LAI Versus Quetiapine)
Description	Relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. The relapse rate in each treatment arm was estimated using the Kaplan-Meier method.
Time Frame	Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and who had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI arm and 11 of the quetiapine arm.

Arm/Group Title	Risperidone LAI	Quetiapine
Arm/Group Description	intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral, target dose of 300-400 mg b.i.d. or t.i.d.
Measure Participants	327	326
Mean (Standard Deviation) [days]	607 (11.4)	533 (15.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI, Quetiapine
	Comments	Null hypothesis was that there is no difference in treatment effect between risperidone LAI and quetiapine by mean relapse free period; given a estimated relapse rate of 30% for risperidone LAI and 42% for quetiapine, with 80% power and 5% 2-tailed significance level, 251 subjects were needed per treatment arm. To adjust for an estimated 20% discontinuations for reasons other than relapse, 628 subjects in total were needed. Actual relapse rates were 17% (risperidone LAI) and 31% (quetiapine).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	threshold for significance: 0.05 (2-sided)
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Mean Relapse Free Period (Exploratory/Aripiprazole)
Description	As for risperidone and quetiapine, relapse was defined as meeting any of the predefined criteria (adapted from Csernansky et al., 2002) on 2 consecutive evaluations during treatment, 3 to 5 days apart. Since aripiprazole was new on the market at the time the study was conducted, this aripiprazole analysis was exploratory.
Time Frame	Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and who had at least 1 efficacy assessment after baseline. This excluded 1 subject of the aripiprazole arm.

Arm/Group Title	Aripiprazole
Arm/Group Description	oral, recommended maintenance dose of 10-30 mg q.d.
Measure Participants	44
Mean (Standard Error) [days]	314 (20.4)

3. Secondary Outcome

Title	Change From Baseline to Endpoint in Total Positive and Negative Syndrome Scale (PANSS) Score
Description	The neuropsychiatric symptoms of schizophrenia were assessed by means of the 30-item PANSS scale. The PANSS scale provides a total score (sum of the scores of all 30 items) and scores for 3 subscales, i.e., the positive subscale (7 items), the negative subscale (7 items), and the general psychopathology subscale (16 items). Each item of the scale is to be scored on a scale of 1 (absent) to 7 (extreme).
Time Frame	Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Week 104 or earlier)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI, 11 of the quetipaine, and 1 of the aripiprazole arm. One additional subject in each the risperidone LAI and quetiapine arm did not have PANSS data.

Arm/Group Title	Risperidone LAI	Quetiapine	Aripiprazole
Arm/Group Description	Risperidone Long Acting Injectable (LAI) intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral Quetiapine, target dose of 300-400 mg twice daily (b.i.d.) or three times daily (t.i.d.)	oral Aripiprazole, recommended maintenance dose of 10-30 mg once daily (q.d.)
Measure Participants	326	325	44
Mean (Standard Deviation) [units on a scale]	-9.3 (25.65)	-1.1 (26.28)	-7.7 (27.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI, Quetiapine
	Comments	Between-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the Last Observation Carried Forward (LOCF) principle, i.e., it was defined as the last available visit during the study with non-missing data for a parameter (excluding the baseline value).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI
	Comments	Within-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Quetiapine
	Comments	Within-group comparison of the change from baseline to endpoint in total PANSS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1026
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

4. Secondary Outcome

Title	Change From Baseline to Endpoint in Clinical Global Impression Scale (CGI) Score
Description	The 7-point CGI scale of Severity (CGI-S) was used to assess the severity of a subject's psychotic condition (0= normal, not at all ill, 1= borderline, etc. and 6= among the most extremely ill subjects).
Time Frame	Assessed at each visit from the moment the subject was randomized to a treatment arm (baseline visit) until the end of treatment (Month 24 or earlier)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI arm, 11 of the quetipaine arm, and 1 of the aripiprazole arm. One additional subject in the risperidone LAI arm did not have CGI data.

Arm/Group Title	Risperidone LAI	Quetiapine	Aripiprazole
Arm/Group Description	Risperidone Long Acting Injectable (LAI) intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral Quetiapine, target dose of 300-400 mg twice daily (b.i.d.) or three times daily (t.i.d.)	oral Aripiprazole, recommended maintenance dose of 10-30 mg once daily (q.d.)
Measure Participants	326	326	44
Mean (Standard Deviation) [units on a scale]	-0.3 (1.25)	0.1 (1.24)	-0.1 (1.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI, Quetiapine
	Comments	Between-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI
	Comments	Within-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Quetiapine
	Comments	Within-group comparison of the change from baseline to endpoint in CGI-S score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0446
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

5. Secondary Outcome

Title	Change From Baseline to Endpoint in Short-Form Health Survey 12 (SF-12) Scores
Description	Quality of life was assessed by means of the 12-item SF-12® survey. Two parameters, i.e., PCS (physical component summary) and MCS (mental component summary) were calculated. Both components scores range from 0 to 100 with higher scores indicating better QOL.
Time Frame	Assessed at the moment the subject was randomized to a treatment arm (baseline visit) and after 1, 3, 6, 12, 18, and 24 months of treatment

Outcome Measure Data

Analysis Population Description

Efficacy analysis set, defined as all subjects who received at least 1 dose of study medication and had at least 1 efficacy assessment after baseline. This excluded 2 subjects of the risperidone LAI, 11 of the quetipaine, and 1 of the aripiprazole arm. An additional 32, 32, and 2 subjects in the respective arms did not have SF-12 data.

Arm/Group Title	Risperidone LAI	Quetiapine	Aripiprazole
Arm/Group Description	Risperidone Long Acting Injectable (LAI) intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks	oral Quetiapine, target dose of 300-400 mg twice daily (b.i.d.) or three times daily (t.i.d.)	oral Aripiprazole, recommended maintenance dose of 10-30 mg once daily (q.d.)
Measure Participants	295	294	42
PCS score	2.1 (9.04)	1.0 (9.31)	2.4 (10.36)
MCS score	3.2 (10.43)	2.7 (10.88)	4.9 (12.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI, Quetiapine
	Comments	Between-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0941
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI
	Comments	Within-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Quetiapine
	Comments	Within-group comparison of the change from baseline to endpoint in PCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1146
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI, Quetiapine
	Comments	Between-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5589
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Risperidone LAI
	Comments	Within-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Quetiapine
	Comments	Within-group comparison of the change from baseline to endpoint in MCS score. The endpoint of the study was based on the LOCF principle.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The statistical test was interpreted at the 5% significance level.
	Method	Wilcoxon signed-rank test
	Comments

Adverse Events

Time Frame	All Adverse Events (AEs) occurring between the first study-related procedure, i.e. screening visit, and 6 weeks after the last injection of risperidone LAI or the last intake of quetiapine or aripiprazole (24 months after baseline) were reported.
Adverse Event Reporting Description	AEs described hereafter are treatment-emergent AEs, defined as AEs that were new in onset or aggravated in severity following treatment start.
Arm/Group Title	Risperidone LAI		Quetiapine		Aripiprazole
Arm/Group Description	Risperidone Long Acting Injectable (LAI) intramuscular injection, dose of 25, 37.5, or 50 mg every 2 weeks		oral Quetiapine, target dose of 300-400 mg twice daily (b.i.d.) or three times daily (t.i.d.)		oral Aripiprazole, recommended maintenance dose of 10-30 mg once daily (q.d.)
All Cause Mortality
	Risperidone LAI		Quetiapine		Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Risperidone LAI		Quetiapine		Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/329 (19.1%)		77/337 (22.8%)		7/45 (15.6%)
Blood and lymphatic system disorders
Acquired methaemoglobinaemia	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Refractory anemia	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Cardiac disorders
Acute myocardial infarction	0/329 (0%)		0/337 (0%)		1/45 (2.2%)
Myocardial infarction	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Endocrine disorders
Hypothyroidism	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Constipation	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Gastic ulcer	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Inguinal hernia	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Peptic ulcer perforation	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
General disorders
Asthenia	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Condition aggravated	1/329 (0.3%)		2/337 (0.6%)		0/45 (0%)
Infections and infestations
Anal abscess	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Anal fistula	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Bronchitis	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Pneumonia	2/329 (0.6%)		1/337 (0.3%)		0/45 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Ankle fracture	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Brain contusion	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Drug toxicity	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Fall	1/329 (0.3%)		1/337 (0.3%)		0/45 (0%)
Head injury	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Joint dislocation	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Lung injury	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Multiple fractures	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Poisoning	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Tibia fracture	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Wrist fracture	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Investigations
Drug level decreased	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	1/329 (0.3%)		1/337 (0.3%)		0/45 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cyst	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Ovarian cancer	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Uterine leiomyoma	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Nervous system disorders
Akathisia	1/329 (0.3%)		1/337 (0.3%)		0/45 (0%)
Cerebrovascular accident	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Coma	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Dizziness	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Epilepsy	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Headache	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Ischaemic stroke	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Parkinsonism	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Status epilepticus	0/329 (0%)		0/337 (0%)		1/45 (2.2%)
Psychiatric disorders
Abnormal behavior	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Acute psychosis	1/329 (0.3%)		2/337 (0.6%)		0/45 (0%)
Affect lability	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Aggression	3/329 (0.9%)		1/337 (0.3%)		0/45 (0%)
Agitation	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Alcoholism	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Anxiety	1/329 (0.3%)		5/337 (1.5%)		0/45 (0%)
Completed suicide	2/329 (0.6%)		1/337 (0.3%)		0/45 (0%)
Delirium	1/329 (0.3%)		0/337 (0%)		1/45 (2.2%)
Delusion	1/329 (0.3%)		4/337 (1.2%)		1/45 (2.2%)
Depression	2/329 (0.6%)		3/337 (0.9%)		0/45 (0%)
Depression suicidal	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Disturbance in social behavior	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Hallucination	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Insomnia	2/329 (0.6%)		3/337 (0.9%)		0/45 (0%)
Irritability	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Major depression	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Mental disorder	2/329 (0.6%)		1/337 (0.3%)		0/45 (0%)
Panic disorder	2/329 (0.6%)		0/337 (0%)		0/45 (0%)
Psychotic disorder	8/329 (2.4%)		14/337 (4.2%)		2/45 (4.4%)
Restlessness	0/329 (0%)		2/337 (0.6%)		0/45 (0%)
Schizoaffective disorder	1/329 (0.3%)		7/337 (2.1%)		0/45 (0%)
Schizophrenia	14/329 (4.3%)		23/337 (6.8%)		0/45 (0%)
Schizophrenia, disorganized type	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Schizophrenia, paranoid type	4/329 (1.2%)		4/337 (1.2%)		0/45 (0%)
Self injurious behavior	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Sleep disorder	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Suicidal ideation	5/329 (1.5%)		1/337 (0.3%)		0/45 (0%)
Suicide attempt	5/329 (1.5%)		2/337 (0.6%)		0/45 (0%)
Suspiciousness	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Renal and urinary disorders
Renal failure acute	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Reproductive system and breast disorders
Ovarian cyst	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/329 (0%)		0/337 (0%)		1/45 (2.2%)
Chronic obstructive airways disease	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Respiratory failure	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Skin and subcutaneous tissue disorders
Urticaria	0/329 (0%)		1/337 (0.3%)		0/45 (0%)
Social circumstances
Family stress	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Social problem	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Surgical and medical procedures
Cyst removal	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Surgery	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Vascular disorders
Deep vein thrombosis	1/329 (0.3%)		0/337 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Risperidone LAI		Quetiapine		Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	201/329 (61.1%)		213/337 (63.2%)		28/45 (62.2%)
Endocrine disorders
Hyperprolactinaemia	43/329 (13.1%)		5/337 (1.5%)		0/45 (0%)
Gastrointestinal disorders
Nausea	1/329 (0.3%)		6/337 (1.8%)		5/45 (11.1%)
General disorders
Asthenia	2/329 (0.6%)		11/337 (3.3%)		3/45 (6.7%)
Investigations
Weight decreased	1/329 (0.3%)		6/337 (1.8%)		3/45 (6.7%)
Weight increased	23/329 (7%)		20/337 (5.9%)		2/45 (4.4%)
Nervous system disorders
Dizziness	2/329 (0.6%)		15/337 (4.5%)		4/45 (8.9%)
Headache	19/329 (5.8%)		16/337 (4.7%)		5/45 (11.1%)
Somnolence	6/329 (1.8%)		38/337 (11.3%)		0/45 (0%)
Psychiatric disorders
Anxiety	39/329 (11.9%)		30/337 (8.9%)		7/45 (15.6%)
Delusion	4/329 (1.2%)		4/337 (1.2%)		4/45 (8.9%)
Depression	15/329 (4.6%)		16/337 (4.7%)		3/45 (6.7%)
Insomnia	36/329 (10.9%)		31/337 (9.2%)		11/45 (24.4%)
Schizophrenia	4/329 (1.2%)		17/337 (5%)		0/45 (0%)
Sleep disorder	8/329 (2.4%)		2/337 (0.6%)		3/45 (6.7%)
Tension	14/329 (4.3%)		14/337 (4.2%)		3/45 (6.7%)

Limitations/Caveats

[Not Specified]

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.