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 |
Dementia of the Alzheimer’s Type |
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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 | 18.1 |
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 |
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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 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. |
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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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The subject population will include: • Male and female subjects between 55 and 90 years of age, inclusive, at the time of informed consent.
• Subjects with a diagnosis of probable Alzheimer's disease according to the NINCDS-ADRDA criteria.
• Subjects with a MMSE score of 5 to 22, inclusive, at the screening and baseline visits.
• Subjects must have a previous MRI or CT scan of the brain, which was performed after the onset of the symptoms of dementia, with findings consistent with a diagnosis of Alzheimer's disease.
• Subjects 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.
• 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 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 (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.
• 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.
• Subjects with onset of symptoms of agitation 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 (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions.
• Subjects who are capable of self-locomotion or locomotion with an assistive device (eg, 4-point walker, wheelchair).
• Subjects willing and able to discontinue all prohibited concomitant medications to meet protocol-required washouts prior to and during the trial period.
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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, HIV-dementia, traumatic brain injury, normal pressure hydrocephalus, or any other specific non-Alzheimer'stype dementia; subjects with a diagnosis of Down syndrome.
• Subjects with a previous MRI or 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.
• Subjects with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
• Subjects who have an insufficient response, based on the investigator's judgment, to 2 or more previous antipsychotic medications for the treatment of agitation associated with Alzheimer's disease.
• Subjects with delirium or history of delirium within the 30 days prior to the screening visit.
• Subjects who have been diagnosed with an Axis I disorder (DSM-IV-TR criteria) including, but not limited to: o Schizophrenia, schizoaffective disorder, or other psychotic disorder not related to dementia o Bipolar I or II disorder, bipolar disorder not otherwise specified o Current major depressive episode. Subjects with major depressive disorder are eligible provided that they have been on a stable dose(s) of antidepressant medication(s) for the 30 days prior to randomization. Please note: antidepressant medications that are CYP2D6 or CYP3A4 inhibitors are prohibited (see Table 4.1-2 for prohibited antidepressant medications).
• 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.
• Subjects who have a current medical condition that requires treatment with an anticoagulant.
• Subjects who have received bapineuzumab, solanezumab, or other immunotherapy, such as vaccines, for the treatment of Alzheimer's disease (through clinical trial or compassionate use program) in the 6 months preceding randomization.
• Subjects who would be likely to require prohibited concomitant therapy during the trial (see Table 4.1-1).
• Subjects who received brexpiprazole in any prior clinical trial or commercially available brexpiprazole (Rexulti®).
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 CMAI subscale scores (aggressive behavior, physically nonaggressive behavior, verbally agitated behavior)
• Change from baseline to Week 12/ET in NPI-NH o 12-item total score o agitation/aggression score
• Clinical Global Impression-Improvement (CGI-I) score, as related to agitation, at Week 12/ET
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 28 |
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 |
Canada |
Finland |
France |
Russian Federation |
Slovenia |
Ukraine |
United Kingdom |
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 eCRF 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 | 3 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |