Treatment for Aggression and Agitation in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine whether this drug can help symptoms of aggression and agitation in participants with Alzheimer's disease.

Detailed Description
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The primary purpose of this study is to help answer the following research questions: Whether this drug can help symptoms of aggression and agitation in participants with Alzheimer's Disease. The safety of this drug and any side effects that might be associated with it. How this drug compares to placebo. During the 12-week period of this study, the participant will have an equal chance of receiving 1 of the 2 treatment groups: active drug or placebo.

Official Title
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Assessment of LY451395 for Neuropsychiatric Symptoms of Aggression and Agitation in Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: LY451395
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Community-dwelling participants with a diagnosis of probable Alzheimer's disease (AD) based on disease criteria from the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Association. Mini Mental State Examination (MMSE) score from 6 to 26 inclusive; Neuropsychiatric Inventory-10 (NPI-10) total score greater than or equal to 10. Are men or women at least 60 years old. Weight greater than or equal to 45 kilograms (kg). Have clinically significant and persistent verbal or physical agitation and/or verbal or physical aggression behaviors that are disruptive to daily functioning or potentially harmful and occurred at least 3 days per week over the past 4 weeks prior to study entry. Understand English. Have a reliable and actively involved caregiver who must be able to communicate in English and be willing to comply with protocol requirements. Exclusion Criteria: Meet DSM-IV-TR or Delirium Rating Scale-Revised-98 criteria for delirium. Does not score ≤4 on the Modified Hachinski Ischemia Scale for vascular dementia. Have a magnetic resonance imaging (MRI) or computer tomography (CT) scan on file since the onset of symptoms of AD and performed within the past 24 months that is inconsistent with a diagnosis of AD. Have a current, required use, or expected use of psychoactive drugs or other medications not allowed in this trial. Have currently active significant medical, neurological, or psychiatric problems that are not allowed in this trial or other brain disorders. Have received acetylcholinesterase inhibitor (AChEIs) or memantine for less than 4 months, or have less than 2 months of stable therapy on these treatments by Visit 2.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY451395<br>3 milligram (mg) LY451395 orally twice daily for 12 weeks; may have been reduced to 1 mg if participant was unable to tolerate | Drug: LY451395<br>* 3 mg LY451395 orally twice daily for 12 weeks; may have been reduced to 1 mg if participant was unable to tolerate<br>* Other names: mibampator;|
| Placebo Comparator: Placebo<br>Placebo orally twice daily for 12 weeks | Drug: Placebo<br>* Placebo orally twice daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the 4-Item Agitation/Aggression Subscale of the Neuropsychiatric Inventory (NPI-4 A/A) at Week 12 | NPI assessed noncognitive psychopathology in participants with Alzheimer's dementia. A 4-item subscale of the standard 12-item NPI measured the neuropsychiatric symptoms of A/A, with items consisting of agitation/aggression, aberrant motor behavior, irritability/emotional lability, and disinhibition. Scores for each subscale (frequency x severity) were calculated to obtain each item score. The total subscale score ranged from 0 to 48, with higher scores indicating more frequent and/or severe A/A symptoms. If a symptom was not present at all, the site would not enter anything for frequency or severity, and a zero would be imputed for that item. Least Squares (LS) Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline NPI-4 A/A, and baseline-by-visit interaction. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in 10-Item Version of Neuropsychiatric Inventory (NPI-10) at Week 12 | NPI assessed noncognitive psychopathology in participants with Alzheimer's dementia. A 10-item scale of the standard 12-item NPI measured neuropsychiatric symptoms minus the appetite and sleep disturbance items. Scores for each subscale (frequency × severity) were calculated to obtain the item score. The total subscale score ranged from 0 to 120, with higher scores indicating more frequent and/or severe A/A symptoms. If a symptom was not present at all, the site would not enter anything for frequency or severity, and a zero would be imputed for that item. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline NPI-10, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in the Neuropsychiatric Inventory (NPI) Depression Domain at Week 12 | NPI Depression domain was an item of the standard 12-item NPI that measured depression in participants with Alzheimer's dementia. Scores for each subscale (frequency × severity) were calculated to obtain the item score, which ranged from 0 to 12 with higher scores indicating more frequent and/or severe neuropsychiatric symptoms. If a symptom was not present at all, the site would not enter anything for frequency or severity, and a zero would be imputed for that item. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline NPI depression, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in the Neuropsychiatric Inventory (NPI) Psychosis Subscale Score at Week 12 | The NPI Psychosis subscale score was the sum of the delusions and hallucinations items of the standard 12-item NPI that measured psychosis symptoms in participants with Alzheimer's dementia. Scores for each subscale (frequency x severity) were calculated for each item score and ranged from 0 to 24 with higher scores indicating more frequent and/or severe neuropsychiatric symptoms. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline NPI psychosis, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in Cohen-Mansfield Agitation Inventory-Community Version (CMAI-C) at Week 12 | CMAI-C is the Cohen-Mansfield Agitation Inventory - Community Version, and it contained 36 questions. The first 35 items were rated from 1 (never) to 7 (several times per hour) and the last item asked if there was any other inappropriate behavior, with a free text field to specify the behavior. The total score ranged from 7 to 245 (7 x 35), with higher scores reflecting more severe agitation. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline CMAI-C, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) at Week 12 | CSDD was a 19-item, clinician-rated scale designed to measure the presence and severity of depressive symptoms in dementia participants. Symptoms were rated as absent, mild/intermittent, or severe. Scores ranged from 0 to 38; scores of 8 or more suggested clinical depression. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline CSDD, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in Total T-Score in the Frontal System Behaviors Scale (FrSBe) at Week 12 | FrSBe was a 46-item, caregiver-rated scale that assessed behaviors associated with damage to the frontal lobes and frontal systems of the brain, including executive function, disinhibition, and apathy. Raw scores were normalized to T-scores based on gender, education, and age. Higher T scores represent a worse outcome. A score of 50 reflects a normative sample, and T scores at or above 65 are considered clinically significant. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline FrSBe, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in Clinical Global Impression-Severity-Agitation/Aggression (CGI-S-A/A) at Week 12 | CGI-S-A/A was a 7-point, single-item rating scale for overall severity of symptoms based on the investigator's general clinical experience with a similar participant population. This Likert scale ranged from 0 (normal) to 7 (most severely ill). LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline CGI-S-A/A, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in Clinical Global Impression-Severity-Global Functioning (CGI-S-GF) at Week 12 | CGI-S-GF was a 7-point, single-item rating scale for overall functioning based on the investigator's general clinical experience with a similar participant population. This Likert scale ranged from 0 (normal) to 7 (most severely ill). LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline CGI-S-GF, and baseline-by-visit interaction. | Baseline, Week 12 | 
| Mean Change From Baseline in the 14-Item Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog14) at Week 12 | ADAS-Cog14, a 14-item rating scale, measured the severity of cognitive dysfunction in persons with AD. Scores ranged from 0 to 90, with a higher score indicating worse cognitive functioning. LS Mean value was adjusted for NPI strata, treatment, pooled site, visit, treatment-by-visit, baseline ADAS-Cog, and baseline-by-visit interaction. | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Agitation and Aggression