E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Chronic, debilitating mental illness characterized by disturbances in thinking, emotional reaction, and behavior |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039626 |
E.1.2 | Term | Schizophrenia |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | 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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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of adjunctive pimavanserin compared with adjunctive placebo on global impression of severity of illness, global improvement of symptoms of illness, personal and social performance, and response to treatment in adults experiencing negative symptoms of schizophrenia |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, ≥18 and ≤55 years of age at the time of Screening 2. Able to understand and provide signed informed consent 3. Able to sign and date a request for medical records and/or subject privacy form if applicable according to local regulations 4. In the Investigator’s opinion, is able to understand the nature of the trial, follow protocol requirements, be willing to comply with study drug administration, and discontinue prohibited concomitant medications 5. Has a caregiver or some other identified responsible person (e.g., family member, social worker, caseworker, or nurse) considered reliable by the Investigator in providing support to the subject to help ensure compliance with study treatment, study visits, and protocol procedures, and who is also able to provide input helpful for completing study rating scales 6. Able to complete subject-reported outcome measures, can be reliably rated on assessment scales, and is willing to participate in audio recording of assessment scales and in an unrecorded telemedicine interview 7. Diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (confirmed using a customized module of the Structured Clinical Interview for DSM-5, Clinical Trials Version [SCID 5 CT]) 8. Diagnosis of schizophrenia made ≥1 year prior to Screening 9. Score ≥20 on the sum of the 7 PANSS Marder negative factor items at Screening and Baseline AND Score ≥4 on at least 3, or ≥5 on at least 2, of the 7 PANSS Marder negative factor items 10. Score ≤22 on the sum of the 8 PANSS Marder positive factor items AND PANSS score where no more than two of the following items have a score of 4 and none of the following items has a score ≥5 at both Screening and Baseline: • P1 (delusions) • P3 (hallucinatory behavior) • P4 (excitement) • P6 (suspiciousness/persecution) • P7 (hostility) 11. A Clinical Global Impression of Schizophrenia Scale–Severity (CGI-SCH-S) for the negative symptoms of schizophrenia score ≥4 (moderately ill or worse) at Screening and Baseline 12. Has been treated with an adequate dose of an antipsychotic within the dose range recommended according to the local prescribing information for at least 8 weeks prior to Screening and remaining at the same dose during the Screening Period 13. The antipsychotic with which the subject is being treated must be one of the antipsychotics listed below: • Aripiprazole o Aripiprazole long-acting injectables o Abilify Maintena® • Aristada® • Asenapine • Brexpiprazole • Cariprazine • Lurasidone • Olanzapine • Risperidone • Risperidone long-acting injection • Paliperidone extended release (ER) (≤9 mg) • Paliperidone palmitate o Invega Sustenna® (≤156 mg) o Invega Trinza® (≤546 mg) o Trevicta® (≤350 mg) o Xeplion® (≤100 mg) 14. If taking an oral antipsychotic, no dose change within 4 weeks prior to Screening or during the Screening Period 15. If taking a long-acting injectable antipsychotic, no dose change within 16 weeks prior to Screening or during the Screening Period 16. If taking an antidepressant medication or an anxiolytic medication, no dose change within 4 weeks of Screening or during the Screening Period (see also Appendix A for restrictions/prohibitions during the study) 17. Must be medically stable (including no recent hospitalization for exacerbation of psychiatric disorder) and has been medically stable for at least 12 weeks prior to Screening, in the opinion of the Investigator 18. If the subject is female, she must not be pregnant or breastfeeding. She must also be of non-childbearing potential (defined as either surgically sterilized or at least 1 year postmenopausal) OR must agree to use TWO clinically acceptable methods of contraception, or be abstinent for at least 1 month prior to Visit 2 (Baseline visit), during the study, and for 41 days following completion of the study. Abstinence as a method of contraception is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. This option is usually made for a specific moral, religious, legal, or health reason. If heterosexual intercourse does occur, two acceptable methods of birth control are required. Acceptable methods of contraception include the following: a. A barrier method (Condom, diaphragm, or cervical cap with spermicide) b. Hormonal contraception, including oral, injectable, transdermal, or implantable methods c. Intrauterine device (IUD) Only one of the two clinically acceptable methods can be a hormonal method. All female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine pregnancy test at Baseline. Note: Specific contraceptive methods are not required for male subjects with partners of childbearing potential, but may be used as a general precaution. |
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E.4 | Principal exclusion criteria |
1. Based on the SCID-5-CT, has a current comorbid psychiatric disorder other than schizophrenia (e.g., bipolar disorder, obsessive compulsive disorder, substance abuse) or a disorder that would interfere with the ability to complete study assessments (e.g., intellectual disability) 2. Score ≥2 for two or more movements or a score of 3 or 4 for any single movement on the Abnormal Involuntary Movement scale (AIMS) 3. Total score ≥2 on the Barnes Akathisia Rating Scale (BARS) 4. Total score ≥5 on the Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 5. Calgary Depression Scale for Schizophrenia (CDSS) score ≥9 at both Screening and Baseline 6. Is at a significant risk of suicide (e.g., answers “Yes” to suicidal ideation question 4 or 5 [current or over last 6 months] or answers “Yes” to suicidal behavior questions on the C-SSRS [over last 6 months]), in the opinion of the Investigator 7. Has a significant risk of violent behavior in the opinion of the Investigator 8. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to randomization (other than caffeine and/or nicotine) 9. A confirmed urine (toxicity) drug screen result at Screening or Baseline that indicates the presence of any tested prohibited substance of potential abuse, including marijuana 10. Subject was treated with two or more antipsychotics, for any indication, within 8 weeks prior to Screening 11. Laboratory testing confirms the absence of the main antipsychotic 12. Is taking a medication or drug or other substance that is prohibited according to this protocol, including medications that prolong the QT interval, strong cytochrome P450 (CYP) 3A4 enzyme (CYP3A4) inhibitors and inducers 13. Known family or personal history or symptoms of long QT syndrome or risk factors for torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval 14. Has an ECG result at Screening or Baseline that meets one of the following exclusionary conditions: • If QRS interval <120 ms then a QTcF ≥460 ms is exclusionary • If QRS interval ≥120 ms then a QTcF ≥480 ms is exclusionary 15. Current evidence, or history within the previous 12 weeks prior to Screening, of a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that in the judgment of the Investigator would jeopardize the safe participation of the subject in the study 16. Has moderate to severe congestive heart failure (New York Heart Association [NYHA] class III and class IV) 17. Has a history of myocardial infarction within 6 months prior to enrollment 18. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening 19. Has a clinically significant thyroid function test result at Screening as defined by abnormal thyroid stimulation hormone (TSH) that reflexes to abnormal thyroxine (T4). If TSH is abnormal and the reflex free T4 is normal, the subject may be enrolled. 20. Has clinically significant laboratory abnormalities that in the judgment of the Investigator or Medical Monitor would jeopardize the safe participation of the subject in the study 21. Known to be positive for hepatitis C virus (HCV) or human immunodeficiency virus (HIV) 22. Has a body mass index (BMI) <19 or ≥35 at Screening 23. Has a history of neuroleptic malignant syndrome 24. Is breastfeeding or lactating 25. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 26. Has previously been randomized in any prior clinical study with pimavanserin, and/or received any other investigational (either approved or unapproved) drug within 30 days or 5 half-lives (whichever is longer) prior to Screening 27. Has any condition that, in the opinion of the Investigator, would interfere with the ability to comply with study instructions, or that might confound the interpretation of the study results or put the subject at undue risk 28. Is an employee of Acadia, or has a family member who is an employee of Acadia 29. Has participated in >2 pharmaceutical clinical research studies within the previous 2 years 30. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the study 31. Subject has had a social hospitalization, defined as admission to the hospital as a result of inadequate family support or care at the subject’s primary residence, during the 8 weeks prior to screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from Baseline to Week 26 in the Negative Symptom Assessment–16 (NSA 16) total score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary Endpoint: • Change from Baseline to Week 26 in the Clinical Global Impression of Schizophrenia Scale–Severity (CGI SCH S) of negative symptoms score Other Secondary Endpoints • Clinical Global Impression of Schizophrenia Scale–Improvement (CGI SCH I) of negative symptoms score at Week 26 • Proportion of CGI-SCH-I of negative symptoms responders (CGI-SCH-I of negative symptoms score of 1 or 2) at Week 26 • Change from Baseline to Week 26 in the Personal and Social Performance (PSP) scale score • Proportion of NSA-16 responders (≥20% and ≥30% reduction in NSA- 16 total score) at Week 26 • Change from Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) total score • Change from Baseline to Week 26 in PANSS negative subscores • Change from Baseline to Week 26 in PANSS Marder factor (negative symptoms) score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Ukraine |
Russian Federation |
Serbia |
Bulgaria |
Czechia |
Hungary |
Italy |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |