Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia
Summary
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EudraCT number |
2016-003434-24 |
Trial protocol |
HU BG CZ LT PL |
Global end of trial date |
25 Jun 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Nov 2020
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First version publication date |
18 Nov 2020
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Other versions |
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-103-034
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02970292 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Acadia Pharmaceuticals Inc.
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Sponsor organisation address |
3611 Valley Centre Drive, Ste. 300, 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 |
28 May 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 May 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Jun 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 |
The primary objective of the study is to evaluate the efficacy of adjunctive pimavanserin compared with adjunctive placebo in the treatment of schizophrenia
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Protection of trial subjects |
Not applicable
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Background therapy |
Patients were to continue intake of their antipsychotic treatment | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Oct 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 |
Canada: 2
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Country: Number of subjects enrolled |
Russian Federation: 90
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Country: Number of subjects enrolled |
Serbia: 77
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Country: Number of subjects enrolled |
Ukraine: 40
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Country: Number of subjects enrolled |
United States: 71
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Country: Number of subjects enrolled |
Poland: 6
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Country: Number of subjects enrolled |
Bulgaria: 93
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
Hungary: 6
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Country: Number of subjects enrolled |
Lithuania: 9
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Worldwide total number of subjects |
396
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EEA total number of subjects |
116
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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) |
396
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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 |
The study was performed between 26 Oct 2016 (first patient consented) and 25 Jun 2019 (last patient last visit). | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Eligible patients had to be taking an adequate dose of an antipsychotic, in the dose range recommended by the local product information, for >=8 weeks before screening. For patients taking 2 antipsychotics, the main antipsychotic was determined and continued, while the second antipsychotic was discontinued (if clinically appropriate). | ||||||||||||||||||||||||||||||||||||
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 | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pimavanserin | ||||||||||||||||||||||||||||||||||||
Arm description |
Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator’s discretion. Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background, main 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 |
Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator’s discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study.
Each daily dose consisted of 2 individual tablets that were to be taken together at approximately the same time each day as the patient's main antipsychotic.
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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.
Each daily dose consisted of 2 individual tablets that were to be taken together at approximately the same time each day as the patient's main antipsychotic.
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Baseline characteristics reporting groups
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Reporting group title |
Pimavanserin
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Reporting group description |
Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator’s discretion. Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background, main 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 |
Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator’s discretion. Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background, main 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 6 in the Positive and Negative Syndrome Scale (PANSS) Total Score | ||||||||||||||||||
End point description |
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of schizophrenia symptoms. The 30 items are arranged as 7 positive symptom items (P1 to P7), 7 negative symptom items (N1 to N7), and 16 general psychopathology symptom items (G1 to G16). Items are scored over the past week (7 days) on a 7-point scale ranging from 1 (absent) to 7 (extreme). The PANSS total score can range from a minimum of 30 to a maximum of 210, where a higher score signifies greater severity of schizophrenia symptoms.
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End point type |
Primary
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End point timeframe |
From baseline to Week 6
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Notes [1] - 193 at baseline; 173 at Week 6 [2] - 196 at baseline; 189 at Week 6 |
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Statistical analysis title |
Primary analysis | ||||||||||||||||||
Comparison groups |
Pimavanserin v Placebo
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Number of subjects included in analysis |
389
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.094 | ||||||||||||||||||
Method |
Mixed-effects model for repeated measure | ||||||||||||||||||
Parameter type |
Difference in MMRM LSMs | ||||||||||||||||||
Point estimate |
-2.1
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-4.5 | ||||||||||||||||||
upper limit |
0.4 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.24
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End point title |
Change From Baseline to Week 6 in the Clinical Global Impression-Severity (CGI-S) Score | ||||||||||||||||||
End point description |
The CGI-S is a 1-item scale, used to rate the severity of the disorder from 0 (not assessed) to 7 (among the most extremely ill patients). A higher CGI-S score denotes greater severity of the disorder.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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Notes [3] - 193 at baseline; 173 at Week 6 [4] - 196 at baseline; 189 at Week 6 |
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No statistical analyses for this end point |
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End point title |
Change From Baseline (CFBL) to Week 6 in PANSS Subscale Scores | ||||||||||||||||||||||||||||||
End point description |
The Subscale Scores were: the PANSS Positive Subscale Score, PANSS Negative Subscale Score and PANSS General Psychopathological Scale Score.
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of schizophrenia symptoms. The 30 items are arranged as 7 positive symptom items (P1 to P7), 7 negative symptom items (N1 to N7), and 16 General psychopathology symptom items (G1 to G16). Items are scored over the past week (7 days) on a 7-point scale ranging from 1 (absent) to 7 (extreme).
The PANSS positive subscale score can range from 7 to 49; the PANSS negative subscale score can range from 7 to 49; the PANSS general psychopathology scale score can range from 16 to 112.
For each of the subscale scores, a higher score signifies greater severity of schizophrenia symptoms.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 6
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Notes [5] - 193 at baseline; 173 at Week 6 [6] - 196 at baseline; 189 at Week 6 |
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No statistical analyses for this end point |
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End point title |
PANSS Responders | |||||||||||||||
End point description |
Porportion of patients showing a PANSS response of >=20% or >=30% reduction in PANSS total score. PANSS total score reduction signifies improvement.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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No statistical analyses for this end point |
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End point title |
Clinical Global Impression-Improvement (CGI-I) Response | |||||||||||||||
End point description |
The CGI-I is a 1-item scale, used to rate the improvement from 1 (very much improved) to 7 (very much worse). Higher scores denote less improvement.
A CGI-I score of 1 or 2 was counted as response. The Analysis was performed twice; once including missing values as non-responders (MN) and once including only observed cases (OC).
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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Notes [7] - 193 for CGI-I Response (MN); 173 for CGI-I Response (OC) [8] - 196 for CGI-I Response (MN); 189 for CGI-I Response (OC) |
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No statistical analyses for this end point |
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End point title |
Clinical Global Impression-Improvement (CGI-I) Score at Week 6 | |||||||||||||||
End point description |
The CGI-I is a 1-item scale, used to rate the improvement from 1 (very much improved) to 7 (very much worse). Higher scores denote less improvement.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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No statistical analyses for this end point |
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End point title |
Change From Baseline to Week 6 in Personal and Social Performance (PSP) Scale Score | ||||||||||||||||||
End point description |
The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial functioning of patients with schizophrenia. The maximum score is 100. 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 6
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Notes [9] - 193 at baseline; 173 at Week 6 [10] - 196 at baseline; 188 at Week 6 |
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No statistical analyses for this end point |
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End point title |
Drug Attitude Inventory (DAI-10) | ||||||||||||||||||
End point description |
The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a patient who is fully adherent to study medication would answer as "True" and 4 items (2, 5, 6, and 8) that a patient who is fully adherent to study medication would answer as "False." A correct answer is scored +1 and an incorrect answer is scored -1; the total score is derived as overall sum. The score can range from -10 to 10. Positive total scores indicate adherence and negative total scores indicate non-adherence. Higher scores denote better adherence.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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Notes [11] - 193 at baseline; 173 at Week 6 [12] - 196 at baseline; 188 at Week 6 |
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No statistical analyses for this end point |
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End point title |
Change From Baseline to Week 6 in Karolinska Sleepiness Scale (KSS) Score | ||||||||||||||||||
End point description |
The KSS is a self-reported measure of a patient’s level of drowsiness. In this study, drowsiness was to be rated during the last week (7 days). Scoring is based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 (very sleepy, great effort to keep awake, fighting sleep). The maximum score is 9. Higher scores denote more drowsiness.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 6
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Notes [13] - 193 at baseline; 173 at Week 6 [14] - 196 at baseline; 189 at Week 6 |
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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 baseline to Week 6
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Adverse event reporting additional description |
The analysis population were those patients who received at least one dose of the study drug. Patients were classified according to the actual treatment received.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator’s discretion. Thereafter, the daily dose was to remain the same for the remainder of the study. 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 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 main changes were introduced:
- Increase in the number of participating study sites to 70
- Addition of the US Package Insert for NUPLAZID® (pimavanserin)
- Requirement to complete baseline PK sampling before the first dose of study drug; requirement to maintain PK data blinded until the unblinding of the database at the end of the study
- Updates to the timing of study drug administration (at approximately the same time as the main antipsychotic medication; guidance in case of missed doses)
- Prohibition of strong cytochrome CYP3A4 Inhibitors; introduction of stopping rules for CYP3A4 Inhibitors/inducers
- Updates to compliance assessments; introduced possibility to discontinue patients with <80% or >120% compliance from the study
- Requirement to measure vital signs before study drug administration
- Requirement for a screening blood sample to confirm the presence or absence of the main antipsychotic
- Requirement to collect written agreement of the patient's caregiver prior to screening procedures to participate in the study in the caregiver role.
- Update of the PANSS to include the caregiver-reported IQ-PANSS |
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30 Mar 2017 |
The following main changes were introduced:
- Update of the eligibility criteria for age to be ≥18 and ≤55 years
- Addition of PK endpoints
- Update of the independent variables in the statistical model to include baseline CGI-S score and baseline-by-visit interaction for CGI-S and PANSS
- Update of statistical methods to hierarchical testing procedure to control the type 1 error rate across the primary and key secondary endpoint
- Update of the PK statistical method to include the main antipsychotic
- Update to the AE collection period for patients rolling over into study ACP-103-035 |
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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 |