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

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ClinicalTrials.gov Identifier: NCT02970305
Recruitment Status : Completed
First Posted : November 22, 2016
Results First Posted : December 22, 2020
Last Update Posted : December 22, 2020
Sponsor:
Information provided by (Responsible Party):
ACADIA Pharmaceuticals Inc.

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

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Study Type : Interventional  (Clinical Trial)
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 : November 4, 2016
Actual Primary Completion Date : October 16, 2019
Actual Study Completion Date : October 28, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

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




Primary Outcome Measures :
  1. Change From Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) Total Score [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    a. 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

  3. 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
  4. Patient has had a myocardial infarction in the last six months
  5. Patient has a family or personal history or symptoms of long QT syndrome
  6. 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).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02970305


Locations
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Sponsors and Collaborators
ACADIA Pharmaceuticals Inc.
  Study Documents (Full-Text)

Documents provided by ACADIA Pharmaceuticals Inc.:
Study Protocol  [PDF] March 31, 2017
Statistical Analysis Plan  [PDF] May 1, 2019

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Responsible Party: ACADIA Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02970305    
Other Study ID Numbers: ACP-103-038
2016-003436-20 ( EudraCT Number )
First Posted: November 22, 2016    Key Record Dates
Results First Posted: December 22, 2020
Last Update Posted: December 22, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Pimavanserin
Antiparkinson Agents
Anti-Dyskinesia Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin 5-HT2 Receptor Antagonists
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action