Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia (ADVANCE)

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02970305
• Collaborator: (none)
• Enrollment: 403
• Locations: 101
• Arms: 2
• Actual Duration (Months): 35.7
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the efficacy and safety of adjunctive pimavanserin compared with adjunctive placebo in the treatment of the negative symptoms of schizophrenia

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Pimavanserin; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 403 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia
• Actual Study Start Date: Nov 4, 2016
• Actual Primary Completion Date: Oct 16, 2019
• Actual Study Completion Date: Oct 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pimavanserin Drug- pimavanserin 34 mg, 20 mg, or 10 mg taken as two tablets + background antipsychotic, once daily by mouth	Drug: Pimavanserin; Pimavanserin 34 mg, 20 mg, or 10 mg, taken as two tablets, once daily by mouth
Placebo Comparator: Placebo Placebo, taken as two tablets + background antipsychotic, once daily by mouth	Drug: Placebo; Placebo, taken as two tablets, once daily by mouth

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) Total Score [From baseline to Week 26]

   The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia.

Secondary Outcome Measures

1. Change From Baseline to Week 26 in the Personal and Social Performance Scale (PSP) Score [From baseline to Week 26]

   The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial functioning of subjects with schizophrenia. Ratings are based on 4 main areas i.e. (a) socially useful activities, including work and study; (2) personal and social relationships, (3) self-care; and (4) disturbing and aggressive behaviors. The time period assessed is "past month". Higher scores denote better psychosocial functioning

2. Proportion of Negative Symptom Assessment-16 (NSA-16) Responders at Week 26 [From baseline to Week 26]

   The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia. NSA-16 responders were defined as patients with at least 20, 30, 50, or 75% percentage improvement in NSA-16 total score from baseline.

3. Change From Baseline to Week 26 in NSA-16 Global Negative Symptoms Rating [From baseline to Week 26]

   The global negative symptoms rating of the NSA-16 assesses overall severity on a 7-point scale from 1 to 7, with higher scores denoting more severe negative symptoms in schizophrenia.

4. Change From Baseline (CFB) to Week 26 in NSA-16 Domain Scores [From baseline (BL) to Week 26]

   The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 domain scores are the sum of item scores in each domain i.e. communication (min score 4, max score 24), emotion/affect (min 3, max 18), social involvement (min 3, max 18), motivation (min 4, max 24), and retardation (min 2, max 12); with higher scores denoting more severe negative symptoms in schizophrenia.

5. Change From Baseline to Week 26 in the Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH-S) of Negative Symptoms Score [From baseline to Week 26]

   The CGI-SCH-S is a clinician-rated, 7-point scale to evaluate positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the negative symptoms were evaluated. The score could range from 1 (normal, not ill) to 7 (among the most severely ill).

6. Clinical Global Impression of Schizophrenia Scale-Improvement (CGI-SCH-I) of Negative Symptoms Score at Week 26 [From baseline to Week 26]

   The CGI-SCH-I is a clinician-rated, 7-point scale to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The score could range from 1 (very much improved) to 7 (very much worse).

7. Proportion of CGI-SCH-I Responders (CGI-SCH-I Score of 1 or 2) at Week 26; Observed Cases [From baseline to Week 26]

   The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The 7-point scores range from 1 (very much improved) to 7 (very much worse); responders were defined as those with CGI-SCH-I of 1 or 2. The analysis includes observed cases; missing cases were not imputed.

8. Change From Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) Total Score [From baseline to Week 26]

   The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS total score is the sum of scores and ranges from a minimum of 30 to a maximum of 210. Higher scores denote more severe symptoms.

9. Change From Baseline (CFB) to Week 26 in PANSS Subscale Scores [From baseline (BL) to Week 26]

   The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS has 3 subscales that are the sums of the respective item scores, including the positive scale (min 7, max 49), negative scale (min 7, max 49), and general psychopathology scale (min 16, max 112). Higher scores denote more severe symptoms.

10. Change From Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score [From baseline to Week 26]

    The BACS is a performance-based assessment of treatment-related changes in cognition, assessing 6 domains of verbal memory and learning; working memory; motor function; verbal fluency; attention and speed of processing; and executive function. The 6 domains with their raw scores are: verbal memory 0-75; digit sequencing 0-28; token motor 0-100; verbal fluency 0-225; symbol coding 0-110; Tower of London 0-22. For each domain, higher scores reflect better cognition. Raw scores are converted to age and sex-corrected normalized scores. The BACS composite score is calculated as the mean of the normalized scores from the 6 subscale scores, standardized so that the mean of the BACS composite score in the healthy normative sample is 50 and the standard deviation is 10.

11. Change From Baseline to Week 26 in 10-item Drug Attitude Inventory (DAI-10) Score [From baseline to Week 26]

    The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the prescribed medication would answer as "True" and 4 items (2, 5, 6, and 8) that a subject who is fully adherent to the prescribed medication would answer as "False." A correct answer is scored +1 and an incorrect answer is scored -1. The total score is the sum of pluses and minuses, which can range from -10 to 10 in increments of 2. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (non-adherent). Higher scores denote better adherence.

12. Change From Baseline to Week 26 in Karolinska Sleepiness Scale (KSS) Score [From baseline to Week 26]

    The KSS is a self-reported subjective measure of a subject's level of drowsiness. Respondents must choose statements that most accurately describe their level of sleepiness over the past 7 days. Scoring was based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 (very sleepy, great effort to keep awake, fighting sleep). Higher scores denoted more drowsiness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult patients, between 18 and 55 years of age

2. A clinical diagnosis of schizophrenia with a minimum duration of 1 year

3. Has predominant negative symptoms according to predefined study criteria

4. The main background antipsychotic with which the subject is being treated must be one of the antipsychotics listed below:

• Aripiprazole

• Aripiprazole long-acting injectables:

• Abilify Maintena®

• Aristada®

• Risperidone

• Risperidone long-acting injection

• Olanzapine

• Lurasidone

• Cariprazine

• Brexpiprazole

• Asenapine

Exclusion Criteria:

1. Patient has a psychiatric disorder other than schizophrenia

2. A urine drug screen (UDS) result at Baseline that indicates the presence of any tested prohibited substance of potential abuse, except marijuana

1. Patients with a result indicating the presence of marijuana are permitted if they agree to abstain from marijuana use during the study and the medical monitor approves the subject's participation

1. Patient has current evidence of a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies, which would affect the patient's ability to participate in the program

2. Patient has had a myocardial infarction in the last six months

3. Patient has a family or personal history or symptoms of long QT syndrome

4. Patient has been hospitalized due to inadequate family support or care at the patient's primary residence, during the 8 weeks prior to screening

Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all pre-specified entry criteria).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85012
2		Rogers	Arkansas	United States	72758
3		Bellflower	California	United States	90706
4		Lemon Grove	California	United States	91945
5		Norwalk	California	United States	90650
6		San Diego	California	United States	92103
7		San Diego	California	United States	92123
8		Santa Ana	California	United States	92705
9		Torrance	California	United States	90502
10		Hialeah	Florida	United States	33016
11		Lauderhill	Florida	United States	33319
12		Miami	Florida	United States	33122
13		Miami	Florida	United States	33136
14		Tampa	Florida	United States	33613
15		Atlanta	Georgia	United States	30328
16		Atlanta	Georgia	United States	30331
17		Decatur	Georgia	United States	30030
18		Marietta	Georgia	United States	30060
19		Chicago	Illinois	United States	60611
20		Hoffman Estates	Illinois	United States	60169
21		Wichita	Kansas	United States	67214
22		Ann Arbor	Michigan	United States	48105
23		Las Vegas	Nevada	United States	89102
24		Berlin	New Jersey	United States	08009
25		Albuquerque	New Mexico	United States	87109
26		Rochester	New York	United States	14618
27		Charlotte	North Carolina	United States	28211
28		Durham	North Carolina	United States	27704
29		Oklahoma City	Oklahoma	United States	73116
30		Downingtown	Pennsylvania	United States	19335
31		Charleston	South Carolina	United States	29407
32		Irving	Texas	United States	75062
33		Richardson	Texas	United States	75080
34		Plovdiv		Bulgaria	4000
35		Sofia		Bulgaria	1202
36		Sofia		Bulgaria	1408
37		Sofia		Bulgaria	1431
38		Sofia		Bulgaria	1680
39		Targovishte		Bulgaria	7700
40		Tserova Koria		Bulgaria	5047
41		Varna		Bulgaria	9020
42		Penticton	British Columbia	Canada	V2A4M4
43		Chatham	Ontario	Canada	N7L1C1
44		Montréal	Quebec	Canada	H3QA 1A1
45		Toronto		Canada	M6J 1H4
46		Hradec Králové	Vekose	Czechia	50341
47		Plzen		Czechia	31200
48		Praha 10		Czechia	10000
49		Praha 10		Czechia	10600
50		Praha 6		Czechia	16000
51		Říčany		Czechia	25101
52		Kalocsa	Bács-Kiskun Megya	Hungary	6300
53		Budapest	Pest Megye	Hungary	1036
54		Budapest	Pest Megye	Hungary	1083
55		Budapest		Hungary	1084
56		Budapest		Hungary	1135
57		Debrecen		Hungary	4032
58		Gyula		Hungary	5700
59		Pecs		Hungary	7633
60		Białystok		Poland	15-756
61		Bydgoszcz		Poland	85-080
62		Lublin		Poland	20-080
63		Lublin		Poland	20-582
64		Pruszcz Gdański		Poland	83-000
65		Roshchino	Leningrad Region	Russian Federation	188820
66		Plekhanovo	Lipetsk Region	Russian Federation	399313
67		Ekaterinburg		Russian Federation	620030
68		Saint Petersburg		Russian Federation	192019
69		Saint Petersburg		Russian Federation	197341
70		Saint-Petersburg		Russian Federation	193167
71		Saint-Petersburg		Russian Federation	195112
72		Samara		Russian Federation	443016
73		Smolensk		Russian Federation	214019
74		Stavropol		Russian Federation	355000
75		Yaroslavl		Russian Federation	150003
76		Belgrade		Serbia	11 000
77		Belgrade		Serbia	11000
78		Kovin		Serbia	26 220
79		Kovin		Serbia	26220
80		Kragujevac		Serbia	34 000
81		Nis		Serbia	18 000
82		Barcelona		Spain	08830
83		Madrid		Spain	28007
84		Oviedo		Spain	33011
85		Valladolid		Spain	47016
86		Zamora		Spain	49021
87		Dnipro		Ukraine	49005
88		Hlevakha		Ukraine	08631
89		Kharkiv		Ukraine	61068
90		Kherson		Ukraine	73488
91		Kyiv		Ukraine	01133
92		Kyiv		Ukraine	02192
93		Kyiv		Ukraine	04080
94		Kyiv		Ukraine	08631
95		Lviv		Ukraine	79017
96		Lviv		Ukraine	79021
97		Odessa		Ukraine	65014
98		Oleksandrivka		Ukraine	67513
99		Poltava		Ukraine	36013
100		Smila		Ukraine	20708
101		Vinnytsia		Ukraine	21005

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 31, 2017
• Statistical Analysis Plan - May 1, 2019

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02970305
• Other Study ID Numbers: ACP-103-038; 2016-003436-20
• First Posted: Nov 22, 2016
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Schizophrenia; Pimavanserin

Study Results

Participant Flow

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Period Title: Overall Study
STARTED	201	202
COMPLETED	172	174
NOT COMPLETED	29	28

Baseline Characteristics

Arm/Group Title	Pimavanserin	Placebo	Total
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment	Total of all reporting groups
Overall Participants	201	202	403
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.7 (9.37)	36.7 (9.24)	37.2 (9.31)
Sex: Female, Male (Count of Participants)
Female	70 34.8%	65 32.2%	135 33.5%
Male	131 65.2%	137 67.8%	268 66.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.5%	1 0.2%
Asian	2 1%	0 0%	2 0.5%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	1 0.2%
Black or African American	10 5%	15 7.4%	25 6.2%
White	187 93%	186 92.1%	373 92.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.5%	0 0%	1 0.2%
Schizophrenia diagnosis confirmed by SCID-5-CT (Count of Participants)
Count of Participants [Participants]	201 100%	202 100%	403 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) Total Score
Description	The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	61.8 (0.60)	61.0 (0.61)
Change from baseline to Week 26	-10.5 (0.69)	-8.8 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0434
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	Difference in MMRM LSMs
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.8 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.95
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 26 in the Personal and Social Performance Scale (PSP) Score
Description	The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial functioning of subjects with schizophrenia. Ratings are based on 4 main areas i.e. (a) socially useful activities, including work and study; (2) personal and social relationships, (3) self-care; and (4) disturbing and aggressive behaviors. The time period assessed is "past month". Higher scores denote better psychosocial functioning
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	47.2 (0.83)	46.7 (0.76)
Change from baseline to Week 26	8.1 (0.70)	8.4 (0.75)

3. Secondary Outcome

Title	Proportion of Negative Symptom Assessment-16 (NSA-16) Responders at Week 26
Description	The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 total score is the sum of item scores. It can range from 16 to a maximum of 96, with higher scores denoting more severe negative symptoms in schizophrenia. NSA-16 responders were defined as patients with at least 20, 30, 50, or 75% percentage improvement in NSA-16 total score from baseline.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score and had no missing values at Week 26.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	174	173
At least 20% improvement	93 46.3%	84 41.6%
At least 30% improvement	56 27.9%	51 25.2%
At least 50% improvement	21 10.4%	16 7.9%
At least 75% improvement	4 2%	2 1%

4. Secondary Outcome

Title	Change From Baseline to Week 26 in NSA-16 Global Negative Symptoms Rating
Description	The global negative symptoms rating of the NSA-16 assesses overall severity on a 7-point scale from 1 to 7, with higher scores denoting more severe negative symptoms in schizophrenia.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	4.7 (0.05)	4.8 (0.05)
Change from baseline to Week 26	-0.7 (0.06)	-0.7 (0.06)

5. Secondary Outcome

Title	Change From Baseline (CFB) to Week 26 in NSA-16 Domain Scores
Description	The NSA-16 is a semi-structured interview and a validated scale containing 16 items for evaluating negative symptoms of schizophrenia, i.e. the reduction or absence of emotional expression and volitional behaviors normally present in a healthy person. Items are scored based on behaviors during the interview (items 1-4, 6, 7, 9, 11, 15, 16) or previous 7 days (items 5, 8, 10, 12-14) on a 6-point scale from 1 to 6. The NSA-16 domain scores are the sum of item scores in each domain i.e. communication (min score 4, max score 24), emotion/affect (min 3, max 18), social involvement (min 3, max 18), motivation (min 4, max 24), and retardation (min 2, max 12); with higher scores denoting more severe negative symptoms in schizophrenia.
Time Frame	From baseline (BL) to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Communication, BL	12.3 (0.22)	12.3 (0.21)
Communication, CFB to Week 26	-2.4 (0.21)	-2.0 (0.19)
Emotion/affect, BL	12.7 (0.14)	12.5 (0.15)
Emotion/affect, CFB to Week 26	-1.9 (0.17)	-1.6 (0.15)
Social Involvement, BL	13.1 (0.16)	12.6 (0.18)
Social Involvement, CFB to Week 26	-2.0 (0.17)	-1.4 (0.19)
Motivation, BL	16.7 (0.18)	16.6 (0.18)
Motivation, CFB to Week 26	-2.6 (0.20)	-2.2 (0.23)
Retardation, BL	7.0 (0.12)	7.0 (0.12)
Retardation, CFB to Week 26	-1.7 (0.13)	-1.5 (0.13)

6. Secondary Outcome

Title	Change From Baseline to Week 26 in the Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH-S) of Negative Symptoms Score
Description	The CGI-SCH-S is a clinician-rated, 7-point scale to evaluate positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the negative symptoms were evaluated. The score could range from 1 (normal, not ill) to 7 (among the most severely ill).
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	4.6 (0.04)	4.7 (0.04)
Change from baseline to Week 26	-0.6 (0.06)	-0.6 (0.06)

7. Secondary Outcome

Title	Clinical Global Impression of Schizophrenia Scale-Improvement (CGI-SCH-I) of Negative Symptoms Score at Week 26
Description	The CGI-SCH-I is a clinician-rated, 7-point scale to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The score could range from 1 (very much improved) to 7 (very much worse).
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	174	173
Mean (Standard Error) [score on a scale]	3.1 (0.07)	3.1 (0.06)

8. Secondary Outcome

Title	Proportion of CGI-SCH-I Responders (CGI-SCH-I Score of 1 or 2) at Week 26; Observed Cases
Description	The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change from baseline in positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia. For the purpose of this study, only the changes in negative symptoms from baseline were evaluated. The 7-point scores range from 1 (very much improved) to 7 (very much worse); responders were defined as those with CGI-SCH-I of 1 or 2. The analysis includes observed cases; missing cases were not imputed.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug); had a baseline value and at least one post-baseline value for NSA-16 total score; and had no missing values at Week 26.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	174	173
Count of Participants [Participants]	47 23.4%	40 19.8%

9. Secondary Outcome

Title	Change From Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) Total Score
Description	The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS total score is the sum of scores and ranges from a minimum of 30 to a maximum of 210. Higher scores denote more severe symptoms.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	77.2 (0.70)	79.4 (0.62)
Change from baseline to Week 26	-8.7 (0.75)	-8.6 (0.76)

10. Secondary Outcome

Title	Change From Baseline (CFB) to Week 26 in PANSS Subscale Scores
Description	The PANSS is a 30-item scale to evaluate the presence, absence, and severity of schizophrenia symptoms. Items are scored over the past week (7 days) on a 7-point scale from 1 (absent) to 7 (extreme). The PANSS has 3 subscales that are the sums of the respective item scores, including the positive scale (min 7, max 49), negative scale (min 7, max 49), and general psychopathology scale (min 16, max 112). Higher scores denote more severe symptoms.
Time Frame	From baseline (BL) to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Positive subscale, BL	13.1 (0.24)	13.7 (0.22)
Positive subscale, CFB to Week 26	-0.6 (0.19)	-0.8 (0.21)
Negative subscale, BL	27.5 (0.26)	27.5 (0.25)
Negative subscale, CFB to Week 26	-4.0 (0.29)	-3.8 (0.31)
General psychopathology subscale, BL	36.6 (0.44)	38.2 (0.40)
General psychopathology subscale, CFB to Week 26	-4.1 (0.43)	-4.0 (0.43)

11. Secondary Outcome

Title	Change From Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score
Description	The BACS is a performance-based assessment of treatment-related changes in cognition, assessing 6 domains of verbal memory and learning; working memory; motor function; verbal fluency; attention and speed of processing; and executive function. The 6 domains with their raw scores are: verbal memory 0-75; digit sequencing 0-28; token motor 0-100; verbal fluency 0-225; symbol coding 0-110; Tower of London 0-22. For each domain, higher scores reflect better cognition. Raw scores are converted to age and sex-corrected normalized scores. The BACS composite score is calculated as the mean of the normalized scores from the 6 subscale scores, standardized so that the mean of the BACS composite score in the healthy normative sample is 50 and the standard deviation is 10.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score. Analysis only included patients with data/endpoint assessment and additionally excluded patients with raw scores outside of the score range.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	197	199
Baseline	22.94 (1.271)	20.99 (1.198)
Change from baseline to Week 26	3.33 (0.719)	4.16 (0.696)

12. Secondary Outcome

Title	Change From Baseline to Week 26 in 10-item Drug Attitude Inventory (DAI-10) Score
Description	The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the prescribed medication would answer as "True" and 4 items (2, 5, 6, and 8) that a subject who is fully adherent to the prescribed medication would answer as "False." A correct answer is scored +1 and an incorrect answer is scored -1. The total score is the sum of pluses and minuses, which can range from -10 to 10 in increments of 2. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (non-adherent). Higher scores denote better adherence.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	5.7 (0.22)	5.7 (0.23)
Change from baseline to Week 26	0.2 (0.23)	0.2 (0.19)

13. Secondary Outcome

Title	Change From Baseline to Week 26 in Karolinska Sleepiness Scale (KSS) Score
Description	The KSS is a self-reported subjective measure of a subject's level of drowsiness. Respondents must choose statements that most accurately describe their level of sleepiness over the past 7 days. Scoring was based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 (very sleepy, great effort to keep awake, fighting sleep). Higher scores denoted more drowsiness.
Time Frame	From baseline to Week 26

Outcome Measure Data

Analysis Population Description

Patients who were randomised and treated (received at least one dose of study drug) and had a baseline value and at least one post-baseline value for NSA-16 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment	Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
Measure Participants	199	201
Baseline	4.6 (0.11)	4.8 (0.10)
Change from baseline to Week 26	-0.3 (0.12)	-0.6 (0.13)

Adverse Events

Time Frame	From the time of the first dose of study drug until 30 days after the last dose of study drug planned to be administered at Week 26
Adverse Event Reporting Description	The analysis population were all patients randomised and treated (i.e. receiving at least one dose of study drug).
Arm/Group Title	Pimavanserin		Placebo
Arm/Group Description	Treatment was to be started at a daily dose of pimavanserin 20 mg; this dose was to be continued for the first 2 weeks of treatment . Subsequently, during the flexible-dosing period of double-blind treatment period (Weeks 2-8), the dose could be continued unchanged, increased to up to 34 mg daily, or decreased to up to 10 mg daily at the investigator's discretion, based on clinical benefit and safety/tolerability. No dose adjustments were allowed during the fixed-dosing period of the double-blind treatment period (Weeks 8-26). Patients were to continue their background antipsychotic treatment		Pimavanserin matching placebo once daily Patients were to continue their background antipsychotic treatment
All Cause Mortality
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/201 (0%)		0/202 (0%)
Serious Adverse Events
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/201 (2%)		1/202 (0.5%)
Psychiatric disorders
Schizophrenia	4/201 (2%)	4	1/202 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/201 (10%)		19/202 (9.4%)
Nervous system disorders
Headache	13/201 (6.5%)	17	10/202 (5%)	10
Somnolence	11/201 (5.5%)	12	10/202 (5%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigator may publish the study results, relative to his/her own patients, only after review, comment and approval by the sponsor. No publication of confidential information shall be made without the sponsor's Prior written consent. At least 60 days prior to submitting a manuscript or prior to any public presentation, a copy of the manuscript or presentation will be provided to the sponsor for review and comment. The sponsor has 60 days to review and comment