| 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 |
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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 | SOC |
| E.1.2 | Classification code | 10037175 |
| E.1.2 | Term | Psychiatric disorders |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10037177 |
| E.1.2 | Term | Infancy, childhood and adolescence psychiatric disorders NEC |
| 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 pharmacokinetics (PK) following multiple doses of pimavanserin (10, 20, or 34 mg) in adolescents with psychiatric disorders |
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| E.2.2 | Secondary objectives of the trial |
| To assess the safety and tolerability following multiple doses of pimavanserin (10, 20, or 34 mg) in adolescents with psychiatric disorders |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Study Population
1. Male or female subjects between the ages of ≥13 and <18 years (Note: subjects must be <18 years by the end of the study)
2. Is within the 5th to 95th percentile for gender specific weight for-age and height-for-age Growth Charts from the National Center for Health Statistics
3. Is able to understand and provide signed informed assent, (informed consent if emancipated) and have a legal guardian who is able to provide signed informed consent
4. Where applicable, 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
5. In the Investigator’s opinion, the subject and parent/legal guardian are able to understand the nature of the trial, follow protocol requirements (including any inpatient stays required by the Investigator based on the subject’s clinical status), and be willing to comply with study drug administration requirements
Psychiatric Diagnosis and Concomitant Medications
6. Has a diagnosis of schizophrenia based on Diagnostic and Statistical Manual-5 [DSM-5]
7. Is judged by the Investigator to be both clinically stable (i.e., no psychiatric hospitalization within the past 12 weeks of Screening) and is not at imminent risk of suicide or injury to self, others, or property
8. Is on a standard of care psychotropic medication for their psychiatric condition
9. If the subject is taking two psychotropic medications at Screening, the Investigator will determine which psychotropic medication is the main treatment and, only if clinically appropriate, will discontinue the other at least 5 half lives before Baseline
a. Subjects with more than 2 psychotropic medications at Screening are not eligible for the study; see Appendix A for further prohibitions and restrictions for medication use during the study
Contraceptives
10. Female subjects who participate in this study must either be unable to become pregnant (e.g., premenarchal, surgically sterile, etc.) -OR- agree to use a highly effective non-hormonal method of contraception (e.g., intrauterine device, condom or diaphragm with spermicides, or contraceptive sponge) from Day -28 to 45 days after last dose
a. Females of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine dipstick hCG pregnancy test at Baseline (Day 1)
11. Male subjects must agree to use a highly effective form of contraception (i.e., double-barrier method which includes a condom plus diaphragm with spermicide or condom plus spermicide) from Day -1 to 45 days after last dose. Male subjects must also agree to not donate sperm for the duration of the study and until 90 days after the last dose of study drug.
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| E.4 | Principal exclusion criteria |
1. Requires treatment with a medication prohibited by the protocol
2. Is taking more than 2 psychotropic medications at Screening
3. Has a history of mental retardation or persistent neurological symptoms attributable to serious head injury. Past history of febrile seizure or drug induced seizure is not exclusionary.
4. Is at a significant risk of suicide, or is a danger to self or others, in the opinion of the Investigator based upon all available sources of information including C-SSRS at Screening or Baseline and including more than one life-threatening suicide attempt
5. Has a significant risk of violent behavior
6. Has a positive urine drug or alcohol test at Screening or positive urine drug dipstick or breathalyzer alcohol test result at Baseline
7. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to Baseline
8. Consumes either more than 21 units of alcohol per week or 4 units of alcohol per day; 1 unit of alcohol is equivalent to 236 mL of beer, 118 mL of wine, or 130 mL of spirits
9. Excessive use of nicotine-containing products within 30 days before study drug administration or is using or has used topical or oral nicotine preparations for smoking cessation within the past 30 days before study drug administration
10. Consumes greater than 500 mg of caffeine or xanthine-containing products per day
11. Refuses to limit caffeine or xanthine-containing products to no more than 100 mg per day during the study
12. Refuses to abstain from alcohol, grapefruit foods or beverages, or Seville-orange containing foods or beverages, from 48 hours prior to check-in on Day -1 through the end of the study
13. Has any condition that 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
14. Has 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
15. Resting position systolic blood pressure (BP) >149 mmHg or <90 mmHg or semisupine diastolic BP >90 mmHg or <60 mmHg at Screening or at Baseline
16. Has at least one resting heart rate, as measured by ECG machine, <50 beats per minute (bpm) or >100 bpm at Screening (central vendor over-read ECGs) or at Baseline
17. Has a positive hepatitis B surface antigen or hepatitis C antibody test result at Screening
18. At Screening has a known history of a positive Human Immunodeficiency Virus (HIV) test result
19. Female subjects of childbearing potential who have a history of taking hormonal contraceptives within 30 days prior to Baseline (Day -1)
20. Has donated >500 mL of blood within 60 days prior to start of Screening
21. Has donated any plasma within 7 days prior to Baseline (Day -1)
22. Has 1 or more clinical laboratory test value(s) outside the range specified in the protocol, or any other clinically significant laboratory abnormality as determined by the Investigator or Medical Monitor at Screening
23. Has a history or presence in on at least one ECG at Screening (central vendor over-read ECGs) or at Baseline (tracings collected on the study-provided ECG device during the visit), of any of the cardiac conduction abnormalities set forth in protocol. One repeat set of triplicate ECGs is allowed that can occur either at Screening or Baseline, in consultation with the Medical Monitor.
24. Has a known family or personal history or symptoms of long QT syndrome or has a history of cardiac arrhythmias 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
25. Has a history of diabetes mellitus (DM) or a glycosylated hemoglobin (HbA1c) >6.5% at Screening
26. Has a clinically significant thyroid function test result at Screening (as measured by thyroid stimulating hormone [TSH] and reflex free thyroxine [T4]). If TSH is abnormal and the reflex free T4 is normal, the subject may be enrolled.
27. Has a history of neuroleptic malignant syndrome
28. Is breastfeeding or lactating
29. Has a sensitivity to any compound present in pimavanserin or any metabolites or compounds listed as being present in this medication
30. Has received any other investigational (either approved or unapproved) drug within 30 days or 5 half lives (whichever is longer) prior to Screening
31. Is participating in another clinical study of any investigational drug, device, or intervention
32. Has participated in >2 pharmaceutical clinical research studies within 6 months of Screening
33. Has a family member who is an employee of ACADIA
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Single dose (Day 1) PK endpoints are as follows:
• AUC(0-24) (area under the plasma concentration-time curve from 0 to 24 hours)
• AUC(0-24)normalized (AUC0-24 normalized to dose and body weight)
• AUC0-t (area under the plasma concentration-time curve from time 0 to time of the last detectable concentration at time T)
• AUC(0-t)normalized (AUC0-t normalized to dose and body weight)
• Cmax (maximum observed plasma concentration)
• Cmax,normalized (Cmax normalized to dose and body weight)
• Tmax (time to maximum plasma concentration)
Multiple dose (Day 20) PK endpoints are as follows:
• AUCτ (area under the plasma concentration-time curve during one dosing interval at steady state)
• AUCτ,normalized (AUCτ normalized to dose and body weight)
• Cmax-ss (Cmax at steady state)
• Cmax-ss,normalized (Cmax-ss normalized to dose and body weight)
• Rac(AUC) (accumulation ratio based on AUC)
• Rac(Cmax) (accumulation ratio based on Cmax)
• Tmax-ss (Tmax at steady state)
• CL/F (apparent systemic clearance of pimavanserin)
• Vss/F (apparent volume of distribution of pimavanserin at steady state)
Trough level collected on Days 17 through 20 will be used to assess pimavanserin steady state as appropriate.
When possible all noted PK parameters will also be calculated as appropriate for the pimavanserin metabolite (AC-279).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1-2: PK blood samples for pimavanserin and its primary metabolite, AC 279, will be collected predose and 1, 2, 4, 6, 9, 12, 16, 24 hours after pimavanserin administration.
Day 17-19: PK blood samples for pimavanserin and its primary metabolite, AC 279, will be collected predose for trough levels on Day 17 through 19.
Day 20: PK blood samples for steady state profile for pimavanserin and its primary metabolite, AC-279,will be collected on Day 20 predose and 1, 2, 4, 6, 9, 12, 16, 24 hours after last dose of pimavanserin administration
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| E.5.2 | Secondary end point(s) |
The safety assessments will include:
• Incidence and severity of adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs
• Frequency of potentially clinically significant findings on:
o Physical examination findings
o Clinical laboratory test results (to include hematology, serum chemistry, and urinalysis)
o Vital sign measurements
o 12-lead electrocardiograms (ECG) parameters
• Change from Baseline on Udvalg for Kliniske Undersøgelser - side effect rating scale (UKU-SERS) scores
• The incidence of subjects with suicidal ideation or suicidal behavior during the study as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within the whole duration of the study - a screening period lasting 1-28 days (1-4 weeks), a treatment period lasting 21 days (3 weeks), and a follow-up period lasting 28 days (approximately 4 weeks). |
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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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| first administration with adolescents |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Bulgaria |
| Russian Federation |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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