| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic, debilitating mental illness characterized by disturbances in thinking, emotional reaction, and behavior |
|
| 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 |
|
| 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 |
| The primary objective of the study is to evaluate the efficacy of adjunctive pimavanserin compared with adjunctive placebo in the treatment of schizophrenia |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of adjunctive pimavanserin compared to adjunctive placebo in the treatment of schizophrenia |
|
| 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 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 Diagnosis 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 randomization
9. 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. The subject may be taking a second antipsychotic at the time of Screening.
10. If the subject is taking two antipsychotics at Screening, the Investigator will:
• Determine which antipsychotic is the main antipsychotic
• Discontinue the other antipsychotic at least 5 half-lives before randomization
• Discontinue the other antipsychotic only if it is clinically appropriate; the other antipsychotic should not be discontinued solely to make the subject eligible for enrollment in the study
11. The main antipsychotic with which the subject is being treated must be one of the antipsychotics listed below:
• Aripiprazole
• Aripiprazole long-acting injectables
– Abilify Maintena®
– Aristada®
• Asenapine
• Brexpiprazole
• Cariprazine
• Lurasidone
• Olanzapine
• Risperidone
• Risperidone long-acting injection
12. Has had a partial but inadequate response to the antipsychotic treatment
13. If taking an oral antipsychotic, no dose change within 4 weeks prior to Screening or the Screening Period
14. If taking a long-acting injectable antipsychotic, no dose change within 16 weeks prior to Screening or during the Screening Period
15. PANSS total score ≥65 and ≤110 at Screening and Baseline and there is no change in PANSS total score >30% from Screening to Baseline
16. PANSS score ≥4 (moderate or worse) on at least two of the following items at both Screening and Baseline:
• P1 (delusions)
• P3 (hallucinatory behavior)
• P6 (suspiciousness/persecution)
17. A CGI-S score ≥4 (moderately ill or worse) at Screening and Baseline
18. Has a history of response to antipsychotic treatment other than clozapine
19. Must be medically stable and has been medically stable for at least 12 weeks prior to Screening, in the opinion of the Investigator
20. If female, must 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 (e.g., oral, intrauterine device [IUD], diaphragm plus spermicide, injectable, transdermal, or implantable contraception)
• All female subjects must have a negative serum human chorionic gonadotropin
(hCG) pregnancy test at Screening and a negative urine pregnancy test at Baseline |
|
| 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. Has a history of resistance to antipsychotic treatment, as defined by either of the following criteria:
• Failed to show even minimal response to ≥2 adequate antipsychotic medications prescribed at adequate doses for adequate length of time; failure to tolerate a medication does not constitute failure to respond
• History of treatment with clozapine for refractory psychosis or use of clozapine within the past 12 weeks prior to Screening
3. Is at a significant risk of suicide, or is a danger to self or others, in the opinion of the Investigator
4. Has a significant risk of violent behavior in the opinion of the Investigator
5. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to randomization (other than caffeine and/or nicotine)
6. A urine drug screen result at Screening or Baseline that indicates the presence of any tested prohibited substance of potential abuse, except marijuana
• Subjects 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
7. Subject was treated with 3 or more antipsychotics, for any indication, within 8 weeks prior to Screening
8. Laboratory testing confirms the absence of the main antipsychotic
9. 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.
10. Known family or personal history or symptoms of long QT syndrome
11. Has a QRS interval <120 ms and QTcF ≥460 ms OR has a QRS interval ≥120 ms and QTcF ≥480 ms at Screening or Baseline
12. 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
13. Has moderate to severe congestive heart failure (New York Heart Association [NYHA] class III and class IV)
14. Has a history of myocardial infarction within 6 months prior to enrollment.
15. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening
16. Has a clinically significant thyroid function test result at Screening
17. 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
18. Known to be positive for hepatitis C virus (HCV) or human immunodeficiency virus (HIV)
19. Has a body mass index (BMI) <19 or ≥35 at Screening
20. Has a history of neuroleptic malignant syndrome
21. Is breastfeeding or lactating
22. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients
23. 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
24. 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
25. Is an employee of ACADIA, or has a family member who is an employee of ACADIA
26. Has participated in >2 pharmaceutical clinical research studies within the previous 2 years
27. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
Change from Baseline to Week 6 in the Clinical Global Impression – Severity scale (CGI-S) score
Other Secondary Endpoints:
Change from Baseline to Week 6 in PANSS subscores
• Clinical Global Impression – Improvement (CGI-I) score at Week 6
• Proportion of responders at Week 6 according to each of the following:
– PANSS (≥20% and ≥30% reduction in PANSS total score)
– CGI-I (CGI-I score of 1 or 2)
• Change from Baseline to Week 6 in Personal and Social Performance (PSP) scale score
• Change from Baseline to Week 6 in 10-item Drug Attitude Inventory (DAI-10) score
• Change from Baseline to Week 6 in Karolinska Sleepiness Scale (KSS) score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Argentina |
| Bulgaria |
| Chile |
| Czech Republic |
| Germany |
| Poland |
| Russian Federation |
| Slovakia |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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