E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Agitation Associated With Dementia of the Alzheimer’s Type |
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E.1.1.1 | Medical condition in easily understood language |
Agitation in dementia due to Alzheimer's Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
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 | 10012271 |
E.1.2 | Term | Dementia Alzheimer's type |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 confirm the efficacy of brexpiprazole compared with placebo in subjects with Agitation in Alzheimer’s dementia |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of brexpiprazole compared with placebo in subjects with Agitation in Alzheimer’s dementia |
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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 |
An optional pharmacogenomic sample and an optional sample for Future Biospecimen Research will be collected if patients consent. |
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E.3 | Principal inclusion criteria |
1.The investigator must assess the capacity of the subject to provide informed consent during the screening period and throughout the course of the trial. 2.Male and female subjects between 55 and 90 years of age, inclusive, at the time of informed consent. 3.Subjects with a diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA criteria. 4.Subjects with a diagnosis of agitation that meets the IPA provisional definition of agitation 5.Subjects with a MMSE score of 5 to 22, inclusive, at the screening and baseline visits. 6.Subjects with a previous MRI or CT scan of the brain, that was performed after the onset of the symptoms of dementia, with findings consistent with a diagnosis of Alzheimer’s disease. 7.Subjects who are residing at their current location for at least 28 days before screening and are expected to remain at the same location for the duration of the trial. 8.Institutionalized subjects with an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject’s symptoms and has direct observation of the subject’s behavior. The identified caregiver can be a staff member of the institutionalized setting or another individual (eg, family member, family friend, hired professional caregiver) who meets the caregiver requirements. Non-institutionalized subjects may not be living alone and must have an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject’s symptoms and has direct observation of the subject’s behavior. 9.Subjects with a total score (frequency × severity) of ≥ 4 on the agitation/aggression item of the NPI NH (for institutionalized subjects) or the NPI/NPI-NH (for non-institutionalized subjects) at the screening and baseline visits. 10.Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit. 11.Subjects must meet additional predetermined blinded eligibility criteria according to the blinded addendum. 12.Subjects who require pharmacotherapy for the treatment of agitation per the investigator’s judgment, after: •An evaluation for reversible factors (eg, pain, infection, or polypharmacy), and •A trial of nonpharmacological interventions (eg, redirecting behavior, group activities, music therapy). 13.Subjects who are capable of self-locomotion or locomotion with an assistive device (eg, 4-point walker, wheelchair). 14.Subjects willing and able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period. 15.Subjects able to satisfactorily comply with the protocol requirements.
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E.4 | Principal exclusion criteria |
1) Subjects with dementia or other memory impairment not due to Alzheimer’s disease, such as mixed or vascular dementia, dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal dementia, substance-induced dementia, human immunodeficiency virus dementia, traumatic brain injury, normal pressure hydrocephalus, or any other specific non Alzheimer’s-type dementia; subjects with a diagnosis of Down syndrome. 2) Subjects with a previous magnetic resonance imaging (MRI)/computed tomography (CT) scan of the brain, which was performed after the onset of the symptoms of dementia, with findings consistent with a clinically significant central nervous system disease other than Alzheimer’s disease, such as vascular changes (eg, cortical stroke, multiple infarcts), space-occupying lesion (eg, tumor), or other major structural brain disease. Note that for subjects in Germany only, the MRI/CT scan can only be performed if it is standard of care. 3) Subjects with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism. 4) Subjects with delirium or history of delirium within the 30 days prior to the screening visit. 5) Subjects who have received high-dose antipsychotics exceeding the equivalent of ≥ 3 mg of risperidone (eg, ≥ 5 mg of haloperidol, ≥ 375 mg quetiapine, ≥ 10 mg olanzapine, or local equivalent) within 90 days prior to screening. 6) Subjects who have received multiple antipsychotic medications simultaneously for a period of > 7 days within 90 days prior to screening. 7) Subjects with evidence of serious risk of suicide based on the Sheehan Suicidality Tracking Scale (Sheehan-STS), ie, a score of 3 or 4 on any one question 2 through 6 or 11, or a score of 2 or higher on any one questions 1a, 7 through 10, or 12, or who, in the opinion of the investigator, present a serious risk of suicide. 8) Subjects considered in poor general health based on the investigator’s judgment. Examples include subjects who have a recent clinically significant weight loss, chronic dehydration or hypovolemia, poor fluid or nutritional intake, or a recent clinically significant infection, as per the investigator’s judgment.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from baseline to Week 12 in the CMAI total score. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline to Week 12 |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the change from baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to agitation. Secondary efficacy endpoints are as follows: • Change from baseline to Week 12 in CMAI subscale scores (aggressive behavior, physically nonaggressive behavior, verbally agitated behavior) • Change from baseline in CMAI total score for each trial visit during the double-blind treatment period • Change from baseline in CGI-S for each trial visit during the double-blind treatment period • Clinical Global Impression Improvement of Illness (CGI-I) score at each trial visit during the double-blind treatment period • CMAI-based responder analysis as described in the statistical analysis plan (SAP) • CGI-I responder analysis as described in the SAP
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• CGI-S: Change from baseline to Week 12 • CMAI subscale scores : Change from baseline to Week 12 • CMAI total score: Change from baseline for each trial visit during the double-blind treatment period • CGI-S: Change from baseline for each trial visit during the double-blind treatment period • Clinical Global Impression Improvement of Illness (CGI-I) score at each trial visit during the double-blind treatment period
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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 | 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 | 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 | 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
| 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 | 7 |
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 |
Bulgaria |
Hungary |
Serbia |
Slovakia |
Spain |
Ukraine |
United States |
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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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The end of trial date is defined as the last date of contact or the date of final contact attempt from the post-treatment follow-up eSource page for the last subject completing or withdrawing from 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 | 4 |
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 | 4 |