| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hallucinations and Delusions Associated With Dementia-related Psychosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Dementia-related psychosis with experience of hallucinations (seeing, hearing, or otherwise sensing things that are not really there) and/or delusions (false or mistaken beliefs) |
|
| 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 | 10012295 |
| E.1.2 | Term | Dementia of the Alzheimer's type, with delusions |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019077 |
| E.1.2 | Term | Hallucinations |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 relapse prevention in subjects with dementia-related psychosis treated with pimavanserin compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the time to discontinuation of the study for any reason in subjects with dementia-related psychosis treated with pimavanserin compared to placebo |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Pharmacogenomic Assessments.
A single blood draw will be performed for subjects who have signed a separate pharmacogenomics consent form indicating their willingness to have their DNA sample stored for possible future genetic research related to pimavanserin or the indication(s) for which it is developed.
|
|
| E.3 | Principal inclusion criteria |
1. Is a male or female ≥50 and ≤90 years of age
2. Can understand the nature of the trial and protocol requirements and provide written informed consent
If the subject is deemed not competent to provide informed consent, the following requirements for consent must be met:
a. The subject’s legally acceptable representative (LAR) (or study partner/caregiver, if local regulations allow) must provide written informed consent
b. The subject must provide written (if capable) informed assent
3. Meets criteria for All-cause Dementia according to NIA-AA guidelines (Appendix A)
4. Meets clinical criteria for one of the following disorders, with or without cerebrovascular disease (CVD):
a. Dementia associated with Parkinson’s disease
(Appendix B)
b. Dementia with Lewy bodies (Appendix C)
c. Possible or probable Alzheimer’s disease (Appendix A)
d. Frontotemporal degeneration spectrum disorders, including possible or probable:
i Behavioral variant frontotemporal dementia (Appendix D)
ii Progressive supranuclear palsy (Appendix E)
iii Corticobasal degeneration (Appendix F)
e. Vascular dementia, including post-stroke dementia, multi-infarct dementia and/or subcortical ischemic vascular dementia (SIVD) (Appendix G)
5. Has an MMSE score ≥6 and ≤24
6. Has sufficient verbal and written ability to understand and answer questions and comply with procedures, with corrective measures such as hearing aids and reading glasses if necessary, and is willing and able to participate in all scheduled evaluations and complete all required tests
7. Has had psychotic symptoms for at least 2 months
8. Has all of the following scores at Visit 1 (Screening) and Visit 2 (open-label Baseline):
a. SAPS-H+D total score ≥10; AND
b. CGI-S ≥4 (moderately ill); AND
c. SAPS-H+D global item (H7 or D13) score ≥4 (marked)
9. Has lived at the current place of residence for at least 3 weeks prior to Visit 1 (Screening) and there are no plans to move to a different location
10. Has a designated study partner/caregiver who meets the following requirements:
a. In the Investigator’s opinion, is in contact with the subject frequently enough to accurately report on the subject’s symptoms and whether or not the subject is taking the study drug
b. Is fluent in the local language in which study assessments will be administered
c. Agrees to participate in study assessments and provides written consent to participate in the study
11. Can come to the clinic for study visits with a study partner/caregiver
12. Has an MRI or CT scan of the brain (completed within past 3 years) taken during or subsequent to the onset of dementia. If not available, a non-contrast brain MRI or non-contrast head CT must be done during screening.
13. If the subject is taking a cholinesterase inhibitor, memantine, or both:
a.the dose of the medication(s) must be stable for at least 12 weeks prior to Visit 2 (open-label Baseline) and there must be no current plan to change the dose; OR:
b.if the medication(s) was discontinued, the discontinuation must occur no fewer than 2 weeks prior to Visit 2 (open-label Baseline)
14. If the subject is taking an antipsychotic medication at the time of screening, the antipsychotic must be discontinued 2 weeks or 5 half-lives (whichever is longer) prior to Visit 2. Investigators should not withdraw a subject’s prohibited medication for the purpose of enrolling them into the study unless discontinuation of the medication is deemed to be clinically appropriate (e.g., symptoms are not well-controlled or the subject cannot tolerate the current medication).
15. 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 a clinically acceptable method of contraception or be abstinent, as defined in the informed consent form (ICF), for at least 1 month prior to Visit 2 (open-label Baseline), during the study, and 1 month following completion of the study.
Acceptable methods of birth control include the following:
a.condom, diaphragm, or cervical cap with spermicide
b.Hormonal contraception, including oral, injectable, transdermal, or implantable methods
c.Intrauterine device (IUD) |
|
| E.4 | Principal exclusion criteria |
1Is in hospice or end-of-life care
2.Is confined to bed
3.Requires skilled nursing care
4.Has psychotic symptoms that are primarily attributable to delirium, substance abuse, or a medical or psychiatric condition other than dementia
5.Has a current major depressive episode according to the DSM-5 criteria
6.Has GCAS score of 3 or 4 based on Investigator's assessment of behavior within the 3 months prior to 1 or since-last-visit at V2
7.Has evidence of a non-neuro medical comorbidity or medication use that could impair cognition
8.Has history of ischemic stroke within the last 12 months or any evidence of hemorrhagic stroke
9.Has a known history of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, or unexplained syncope
10.Has atrial fibrillation unless adequately anticoagulated
11.Has any of the following:
a.greater than NYH Class 2 congestive heart failure or
b.grade 2 or greater angina pectoris (by Canadian Cardiovascular Society [CCS] Angina Grading Scale)
c.sustained ventricular tachycardia,
d.ventricular fibrillation, or
e.torsade de pointes, or
f.syncope due to an arrhythmia
g.an implantable cardiac defibrillator
12.Had myocardial infarction within the 6 months prior to V1
13.Has known personal or family history/symptoms of long QT syndrome
14.Has any of the following ECG results at V1 or V2:
a.If the subject is not on citalopram, escitalopram, or venlafaxine:
i. QTcF >450 ms, if QRS duration <120 ms
ii. QTcF >470 ms, if QRS duration ≥120 ms
b. the subject is on citalopram, escitalopram, or venlafaxine:
i.QTcF >425 ms, if QRS duration <120 ms
ii.QTcF >450 ms, if QRS duration ≥120 ms
If the mean QTcF value from the set of ECGs done at Screening is prolonged due to an identifiable cause, and it is medically appropriate to address that cause, a repeat set of triplicate ECGs may be performed during Screening at the discretion of the Medical Monitor.
15.Has heart rate <50 beats per minute. If bradycardia is secondary to iatrogenic or treatable causes and these causes are addressed, a heart rate assessment can be repeated during the screening period.
16.Has significant unstable medical condition that could interfere with subject's ability to complete the study/comply with study procedures
17.Has severe renal impairment, severe or medically significant impairment of hepatic function, and/or a clinically significant laboratory abnormality that in the judgment of the Investigator or Medical Monitor will interfere with the conduct or interpretation of safety or efficacy
18. Has one of the following screening laboratory results:
a. Platelets ≤75,000/mm3
b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female
c. Neutrophils, absolute ≤1000/mm3
d. Aspartate aminotransferase (AST) >2×upper limit of normal
e. Alanine aminotransferase (ALT) >2×upper limit of normal
f. Creatinine ≥2 mg/dL
g. Hemoglobin A1c (HbA1c) ≥8.5%
h. Abnormal free thyroxine (T4)
i. Vitamin B12 deficiency
Laboratory testing may be repeated during Screening at the discretion of the Medical Monitor.
19. Has a history of a positive test result for HIV or hepatitis C
20. Has a clinically significant CNS abnormality that is most likely contributing to the dementia or findings on MRI or CT including:
a. intracranial mass lesion
b. vascular malformation
c.intracranial aneurysm >4 points by PHASES score
d. evidence of >4 hemosiderin deposits
21. Requires treatment with a medication or other substance that is prohibited by the protocol
22. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional weight loss ≥7% of body weight over past 6 months
23. The urine drug screen result at V1 indicates the presence of amphetamine/methamphetamine, barbiturates, cocaine, or phencyclidine. Subjects who test positive for amphetamines or barbituates may be retested during Screening if they agree to abstain from the medication for the length of their participation in the study and if abstinence from medication usage is achieved at least 7 days prior to V1. The repeat Screening test must be negative for them to participate in the study. The presence of benzodiazepines, marijuana, or opiates may not exclude the subject from the study.
24. Has participated in or is participating in a clinical trial of any investigational drug, device, or intervention, within 30 days or 5 half-lives, whichever is longer, of V1 OR has participated in a clinical trial for disease-modifying therapy within 6 months of V1
25. Has previously been enrolled in any prior clinical study with pimavanserin /currently taking pimavanserin
26. Has a significant sensitivity/ allergic reaction to pimavanserin
27. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals Inc.
28. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study for any reason
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time from randomization to relapse in the double-blind period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 38 (end of 26 week double blind period) |
|
| E.5.2 | Secondary end point(s) |
| Time from randomization to discontinuation from the double-blind period for any reason |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 38 (end of 26 week double blind period) |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Italy |
| Poland |
| Serbia |
| Slovakia |
| Spain |
| Ukraine |
| United Kingdom |
| 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
|
| The end of the clinical study will be when the last subject completes the last scheduled assessment (i.e., safety follow-up) |
|
| 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 | |
| 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 | 6 |
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