| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Dementia of the Alzheimer’s Type |
|
| 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 | 17.1 |
| 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 |
|
| 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 compare the efficacy of flexible dosing of brexpiprazole (dose range of 0.5 to 2 mg/day) with placebo in subjects with agitation associated with dementia of the Alzheimer’s type, as assessed by the Cohen Mansfield Agitation Inventory (CMAI) after 12 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of flexible dosing of brexpiprazole (dose range of 0.5 to 2 mg/day) compared with placebo in subjects with agitation associated with dementia of the Alzheimer’s type after 12 weeks of treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The subject population will include:
1. male and female subjects between 55 and 90 years of age (inclusive), who are residing at their current location for at least 14 days before screening and are expected to remain at the same location for the duration of the trial, with a diagnosis of probable Alzheimer's disease according to the NINCDS-ADRDA criteria.
2. Subjects must have a previous magnetic resonance imaging (MRI) or computed tomography (CT).
3. Institutionalized subjects with an identified caregiver who has sufficient contact 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 settings or another individual (e.g., family member, family friend, hired professional caregiver) who meets
the caregiver requirements.
4. Non-institutionalized subjects may not be living alone (see Section 3.3.1.1 for caretaker definition) and must have an identified caregiver who has sufficient contact to describe the subject's symptoms and has
direct observation of the subject's behavior.
5. Subjects must have a previous MRI or CT scan of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with a diagnosis of Alzheimer's disease.
6. Additionally, at both the screening and baseline visits, subjects must have a Mini-Mental State Examination (MMSE) score of
5 to 22, inclusive, and a score of ≥ 4 on the agitation/aggression item of the NPI-NH.
7. The onset of the subject's symptoms of agitation must be at least 2 weeks prior to the screening visit. Subjects who require pharmacotherapy for the treatment of agitation per the investigator's judgment, after an evaluation for reversible factors (e.g., pain, infection, polypharmacy) and trial of
nonpharmacological interventions. |
|
| E.4 | Principal exclusion criteria |
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, or any other
specific non-Alzheimer’s-type dementia; subjects aged 55 years or older with a diagnosis of Down syndrome
Subjects with a previous MRI or CT scan of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with a clinically significant central nervous system disease other than Alzheimer’s disease, such as vascular changes (e.g., cortical stroke, multiple infarcts), space-occupying lesion (e.g., tumor), or other major structural brain disease.
Subjects with a history of stroke, transient ischemic attack, or pulmonary or cerebral embolism.
Subjects with a history of clinically relevant traumatic brain injury with neurological sequelae.
Subjects with a history of a deep venous thrombosis within the 5 years prior to the screening visit.
Subjects with delirium, unless resolved with no symptoms for at least 30 days prior to the screening visit.
Subjects with evidence of serious risk of suicide based on the Sheehan Suicidality Tracking Scale (Sheehan-STS) or who, in the opinion of the investigator, present
a serious risk of suicide.
Subjects considered in poor general health based on the investigator’s judgment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the change from baseline to Week 12/ET in the CMAI total score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy variable is the change from baseline to Week 12/ET in the Clinical Global Impression-Severity of Illness (CGI-S) score, as related to agitation
Change from baseline to Week 12/ET in the following:
- CMAI subscale scores (aggressive behavior, physically nonaggressive behavior, verbally agitated behavior)
- NPI-NH total score, psychosis subscale score(delusions and hallucinations), individual item scores (eg, agitation/aggression, anxiety,irritability/lability), and occupational disruptiveness scores (individual item and total scores) for institutionalized subjects
- Change from baseline to Week 12/ET in NPI-NH total score, psychosis subscale score (delusions and hallucinations), and individual item score (e.g., agitation/aggression, anxiety, irritability/lability), and in NPI distress scores (individual item and total scores), for noninstitutionalized subjects
- CGI-Improvement (CGI-I) score, as related to agitation, at Week 12/ET
-CGI-Efficacy index (CGI-E) score, which is defined as the ratio of current therapeutic effect (as related to agitation) and severity of side effects, at Week 12/ET
Change from baseline to Week 12/ET in the following:
- Modified Nursing Care Assessment Scale (M-NCAS) score ((for institutionalized subjects only))
- Quality of Life in Alzheimer’s Disease(QoL-AD) score
- Nurses’ Observation Scale for Geriatric Patients (NOSGER) score ((for institutionalized subjects only))
- Change from baseline to Week 12/ET in the Resource Utilization in
Dementia (RUD) score
- Safety variables (adverse events, physical examinations, neurological examinations, vital signs, body weight, waist circumference, clinical laboratory tests and ECGs. Other safety variables will include the MMSE score and assessments of suicidality (Sheehan-STS), extrapyramidal symptoms (the Simpson Angus Scale [SAS], the Abnormal Involuntary Movement Scale [AIMS], and the Barnes Akathisia Rating Scale [BARS]
- Determination of brexpiprazole and its major metabolite DM-3411with the collection of pharmacokinetic samples |
|
| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 142 |
| 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 |
| Canada |
| Finland |
| France |
| Slovakia |
| Slovenia |
| 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-trial date is defined as the last date of contact or the date of final contact attempt from the post-treatment follow-up eCRF page for the last subject completing or withdrawing from the trial. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 | 3 |
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