E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Psychosis associated with Alzheimer's disease |
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E.1.1.1 | Medical condition in easily understood language |
Psychosis associated with Alzheimer's disease |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
MedDRA Classification |
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 assess the efficacy of pimavanserin 40 mg compared with placebo in the treatment of patients with Alzheimer’s disease psychosis (ADP). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of pimavanserin in patients with ADP. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients, 50 years of age or older at baseline, with NINCDS-ADRDA defined possible or probable AD 2. Have been a nursing home resident for ≥ 2 weeks prior to Screening and ≥ 4 weeks prior to randomization, not bedridden and expected to remain in the facility throughout the study 3. Have psychotic symptoms that developed after the diagnosis of AD was established. These symptoms must include visual and/or auditory hallucinations, and/or delusions 4. Patient must have actively experienced and verbally communicated psychotic symptoms during the month prior to the Screening visit (SV1) and weekly during the previous 2 weeks prior to Baseline 5. In the opinion of the investigator the patient requires treatment for their ADP symptoms as evidenced by, for example: distress in the subject, excess disability not attributable to factors other than psychosis, disruptive behavior, interference with medical, nursing or rehabilitative care, and/or dangerous to self or others 6. Symptoms must be severe enough at Screening (SV1) and at Baseline to warrant treatment with an antipsychotic agent as documented by Domains A and B of the NPI-NH, and defined as a score of 4 or greater on either the Hallucinations (Frequency x Severity) or Delusions (Frequency x Severity) scales OR a total combined score of 6 or greater 7. Patients on acetylcholinesterase inhibitor (AChEI) therapy and/or memantine must be receiving stable doses for 3 months prior to the Baseline visit and during the study 8. Female patients must 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 (such as oral, intrauterine device [IUD; diaphragm], injectable, transdermal or implantable contraception), for at least one month prior to randomization, during the study, and one month following completion of the study 9. Willing and able to provide informed consent. If patient is unable to provide written consent due to the severity of dementia, consent must be given by a legally authorized representative 10. Subject and staff caregiver acting as informant are willing and able to adequately communicate in English for the purposes of the key endpoint assessments by raters |
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E.4 | Principal exclusion criteria |
1. Have psychotic symptoms (hallucinations and delusions) which are likely a part of a toxic, metabolic or infection-induced delirium/encephalopathy, psychosis due to substance abuse, psychosis associated with schizophrenia, bipolar disorder or psychotic depression 2. The psychotic symptoms occur exclusively during the course of a delirium 3. Have a history of significant psychotic disorders prior to or concomitantly with the diagnosis of Alzheimer’s disease including, but not limited to, schizophrenia or bipolar disorder 4. Have a score on the MMSE of < 1 or > 22 5. Are unable to communicate verbally 6. Have a history of any condition which may prevent the administration or completion of essential study assessments (e.g. cerebrovascular ischemic syndrome/stroke that impairs their ability to complete the MMSE) 7. Using any of the medications prohibited or in a manner otherwise restricted as described in Appendix 2 of the clinical protocol (Prohibited and restricted Concomitant Medications) 8. Current evidence of a serious and/or unstable cardiovascular, respiratory, gastrointestinal, renal, hematologic or other medical disorder, including cancer or malignancies, which would affect the patient’s ability to participate in the study 9. Patient has had a myocardial infarction in the last six months 10. Patient has moderate to severe congestive heart failure (New York Heart Association class III or IV as described in Appendix 1 of the clinical protocol) 11. Known history or symptoms of long QT syndrome 12. Has a Screening and Baseline ECG with Bazett’s corrected QT interval (QTcB) of greater than 460 msec if male or 470 msec if female 13. Has clinically significant laboratory abnormalities that in the judgment of the investigator would jeopardize the safe conduct of the study 14. Patient is pregnant or breastfeeding. Female patients of child-bearing potential must have a negative serum pregnancy test at Screening, and it must be confirmed at Baseline using a dipstick urine pregnancy test 15. Patient has any surgery planned during the screening, treatment or follow-up periods 16. Patient is likely to have an allergy or sensitivity to pimavanserin based on known allergies to drugs of the same class 17. Patient has previously participated in any prior clinical study with pimavanserin, and/or received any other investigational drug within 30 days prior to the Screening Visit 18. Patient is judged by the investigator to be inappropriate for the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Key Efficacy Endpoints: • NPI-NH psychosis subscale (Delusions + Hallucinations Domains A and B) • NPI-NH Agitation/Aggression (Domain C) • NPI-NH Sleep/Nighttime Behavior (Domain K) • Cohen-Mansfield Agitation Inventory – Short Form (CMAI-SF) • Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessments made at baseline then days 15, 29, 43, 64 and 85 |
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E.5.2 | Secondary end point(s) |
Seconday Efficacy Endpoints N/A
EXPLORATORY Efficacy Endpoints • NPI-NH total and all remaining individual behavioral domains • Alzheimer’s Disease Cooperative Study – Activities of Daily Living Instrument (ADCS-ADL) • Change in utilization of rescue medications for behavioral disturbance and sleep • Durability of response to pimavanserin in patients with ADP as measured by change from Day 43 to Day 85 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments made at baseline then days 15, 29, 43, 64 and 85 |
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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 | Yes |
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) | Yes |
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 | 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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 2 |
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 |