Clinical Trial Results:
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
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Summary
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EudraCT number |
2016-003436-20 |
Trial protocol |
HU BG ES CZ PL |
Global end of trial date |
28 Oct 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
30 Jan 2021
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First version publication date |
18 Nov 2020
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ACP-103-038
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02970305 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Acadia Pharmaceuticals Inc.
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Sponsor organisation address |
12830 El Camino Real, Suite 400, San Diego, United States, 92130
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Public contact |
Sr. Dir. Medical Information and Medical Communications, Acadia Pharmaceuticals Inc., 1 8582612897, medicalinformation@acadia-pharm.com
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Scientific contact |
Sr. Dir. Medical Information and Medical Communications, Acadia Pharmaceuticals Inc., 1 8582612897, medicalinformation@acadia-pharm.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Oct 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Oct 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of pimavanserin compared with placebo in the adjunctive treatment of the negative symptoms of schizophrenia
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Protection of trial subjects |
Not applicable
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Background therapy |
Patients were to continue their main background antipsychotic medication | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Nov 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Spain: 13
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Country: Number of subjects enrolled |
Bulgaria: 91
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Country: Number of subjects enrolled |
Czech Republic: 23
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Serbia: 68
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Country: Number of subjects enrolled |
Russian Federation: 100
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Country: Number of subjects enrolled |
Ukraine: 40
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Country: Number of subjects enrolled |
United States: 49
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Worldwide total number of subjects |
403
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EEA total number of subjects |
146
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
403
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
This study enrolled patients with predominant negative symptoms of schizophrenia, using antipsychotic treatment from a protocol-defined list of allowed treatments. The main antipsychotic treatment was to be continued during the study; adjustments to the dose of the main antipsychotic were not permitted after completion of the screening period. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pimavanserin | |||||||||||||||||||||||||||||||||
Arm 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 | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pimavanserin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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).
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Pimavanserin-matching Placebo. Patients were to continue their background main antipsychotic treatment | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Pimavanserin matching placebo once daily
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Baseline characteristics reporting groups
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Reporting group title |
Pimavanserin
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Reporting 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Pimavanserin-matching Placebo. Patients were to continue their background main antipsychotic treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pimavanserin
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Reporting 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 | ||
Reporting group title |
Placebo
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Reporting group description |
Pimavanserin-matching Placebo. Patients were to continue their background main antipsychotic treatment | ||
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End point title |
Change From Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) Total Score | ||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
From baseline to Week 26
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| Notes [1] - 199 at baseline; 174 at Week 26 [2] - 201 at baseline; 173 at Week 26 |
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Statistical analysis title |
Primary analysis | ||||||||||||||||||
Comparison groups |
Placebo v Pimavanserin
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.0434 | ||||||||||||||||||
Method |
Mixed-effects model for repeated measure | ||||||||||||||||||
Parameter type |
Difference in MMRM LSMs | ||||||||||||||||||
Point estimate |
-1.9
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-3.8 | ||||||||||||||||||
upper limit |
-0.1 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.95
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End point title |
Change From Baseline to Week 26 in the Personal and Social Performance Scale (PSP) Score | ||||||||||||||||||
End point 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
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [3] - 199 at baseline; 174 at Week 26 [4] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Proportion of NSA-16 Responders at Week 26 | |||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Change From Baseline to Week 26 in NSA-16 Global Negative Symptoms Rating | ||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [5] - 199 at baseline; 174 at Week 26 [6] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline (CFB) to Week 26 in NSA-16 Domain Scores | ||||||||||||||||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [7] - BL: 199 (E/A, S, M: 198); W26: 174 (E/A: 171, SI, M: 173) [8] - BL: 201 (E/A: 200, SI: 199); W26: 173 (E/A, SI: 172) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline to Week 26 in CGI-SCH-S of Negative Symptoms Score | ||||||||||||||||||
End point description |
The Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH-S) of Negative Symptom scoreis 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).
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [9] - 199 at baseline; 174 at Week 26 [10] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Clinical Global Impression of Schizophrenia Scale-Improvement (CGI-SCH-I) of Negative Symptoms Score at Week 26 | ||||||||||||
End point 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).
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Proportion of CGI-SCH-I Responders (CGI-SCH-I Score of 1 or 2) at Week 26; Observed Cases | |||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change From Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) Total Score | ||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [11] - 199 at baseline; 174 at Week 26 [12] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline (CFB) to Week 26 in PANSS Subscale Scores | ||||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [13] - 199 at baseline, 174 at Week 26 [14] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia (BACS) Score | ||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [15] - 197 at baseline; 173 at Week 26 [16] - 199 at baseline; 170 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline to Week 26 in 10-item Drug Attitude Inventory (DAI-10) Score | ||||||||||||||||||
End point 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 (nonadherent). Higher scores denote better adherence.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 26
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| Notes [17] - 199 at baseline; 174 at Week 26 [18] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline to Week 26 in Karolinska Sleepiness Scale (KSS) Score | ||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Change from baseline to Week 26
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| Notes [19] - 199 at baseline; 174 at Week 26 [20] - 201 at baseline; 173 at Week 26 |
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
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
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Adverse event reporting additional description |
The analysis population were all patients randomised and treated (i.e. receiving at least one dose of study drug).
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Pimavanserin
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Reporting 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 | ||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Pimavanserin-matching Placebo. Patients were to continue their background main antipsychotic treatment | ||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Nov 2016 |
The following key changes were implemented:
- Safety follow-up period extended to 4 weeks
- Number of sites increased to 70
- Inclusion criteria amended to: state that patients must have been medically stable for at least 12 weeks before Screening; remove requirement for abstinence during and at least 1 month after completion of the study
- Exclusion criteria amended to: include history of uncontrolled diabetes mellitus Type 1 or 2 requiring insulin; exclude patients with history of suicide attempts or currently actively suicidal or at imminent risk of self-harm
- Test product updated to include 17 mg tablets and matching placebo
- Dose updated to include pimavanserin (or matching placebo) 34 mg
- Informed consent updated to include written agreement from the patient's caregiver
- Blood sample collection, screening, PK statistical methods updated to confirm presence or absence of the identified main antipsychotic
- Added population PK/PD model for exposure response relationship between pimavanserin plasma concentrations and efficacy and safety parameters
- Prohibition/restriction of drugs prolonging QT interval; prohibition of strong cytochrome CYP3A4 Inhibitors; introduced rules to discontinue CYP3A4 Inhibitors/inducers
- Introduced possibility to discontinue patients with <80% or >120% compliance from the study
- PANSS updated to include the caregiver-reported IQ-PANSS
- Added reporting of overdose within 24 hours of discovery |
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31 Mar 2017 |
- Inclusion criteria amended to: specify age as ≥18 and ≤55 years; delete requirement for ≤10 years treatment with an antipsychotic
- Exclusion criteria amended to: allow patients with presence of marijuana based on laboratory testing (but patient had to abstain from marijuana use during the study); added exclusion criterion of social hospitalization in the last 8 weeks
- Updated data required to be selected at PK sampling
- PK assessment procedures and endpoints updated
Screening period requirements were updated to include subjects up to age ≤55 and
preference for enrollment of an equal number of subjects who are ≤35 and who are
>35 years old.
- Allowed a single documented social hospitalization for a maximum duration of 2 weeks over the course of the study.
- AE collection period updated
- Several updates to statistical methods and testing strategy
- Added anticholinergic restrictions; modified rules for anxiolytics to allow patients on a stable dose at study entry |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
