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

Primary Purpose

Alzheimer's Disease

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

LY451395

Placebo

About this trial

This is an interventional treatment trial for Alzheimer's Disease focused on measuring Agitation and Aggression

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

LY451395

Placebo

Arm Description

3 milligram (mg) LY451395 orally twice daily for 12 weeks; may have been reduced to 1 mg if participant was unable to tolerate

Placebo orally twice daily for 12 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT00843518

First Posted

February 12, 2009

Last Updated

October 23, 2017

Sponsor

Eli Lilly and Company

1. Study Identification

Unique Protocol Identification Number

NCT00843518

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Completed

Study Start Date

February 2009 (undefined)

Primary Completion Date

June 2011 (Actual)

Study Completion Date

June 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Eli Lilly and Company

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer's Disease

Keywords

Agitation and Aggression

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

132 (Actual)

8. Arms, Groups, and Interventions

Arm Title

LY451395

Arm Type

Experimental

Arm Description

3 milligram (mg) LY451395 orally twice daily for 12 weeks; may have been reduced to 1 mg if participant was unable to tolerate

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo orally twice daily for 12 weeks

Intervention Type

Drug

Intervention Name(s)

LY451395

Other Intervention Name(s)

mibampator

Intervention Description

3 mg LY451395 orally twice daily for 12 weeks; may have been reduced to 1 mg if participant was unable to tolerate

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo orally twice daily for 12 weeks

Primary Outcome Measure Information:

Title

Mean Change From Baseline in the 4-Item Agitation/Aggression Subscale of the Neuropsychiatric Inventory (NPI-4 A/A) at Week 12

Description

Time Frame

Baseline, Week 12

Secondary Outcome Measure Information:

Title

Mean Change From Baseline in 10-Item Version of Neuropsychiatric Inventory (NPI-10) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in the Neuropsychiatric Inventory (NPI) Depression Domain at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in the Neuropsychiatric Inventory (NPI) Psychosis Subscale Score at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in Cohen-Mansfield Agitation Inventory-Community Version (CMAI-C) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in Total T-Score in the Frontal System Behaviors Scale (FrSBe) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in Clinical Global Impression-Severity-Agitation/Aggression (CGI-S-A/A) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in Clinical Global Impression-Severity-Global Functioning (CGI-S-GF) at Week 12

Description

Time Frame

Baseline, Week 12

Title

Mean Change From Baseline in the 14-Item Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog14) at Week 12

Description

Time Frame

Baseline, Week 12

10. Eligibility

Sex

All

Minimum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Call 1-877.CTLilly (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM-5PM Easter time (UTC/GMT-5 hours, EST

Organizational Affiliation

Eli Lilly and Company

Official's Role

Study Director

Facility Information:

Facility Name

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85006

Country

United States

Facility Name

City

Costa Mesa

State/Province

California

ZIP/Postal Code

92626

Country

United States

Facility Name

City

Hamden

State/Province

Connecticut

ZIP/Postal Code

06518

Country

United States

Facility Name

City

Orlando

State/Province

Florida

ZIP/Postal Code

32806

Country

United States

Facility Name

City

Tampa

State/Province

Florida

ZIP/Postal Code

33609

Country

United States

Facility Name

City

West Palm Beach

State/Province

Florida

ZIP/Postal Code

33407

Country

United States

Facility Name

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30308

Country

United States

Facility Name

City

Easton

State/Province

Maryland

ZIP/Postal Code

21601

Country

United States

Facility Name

City

Flowood

State/Province

Mississippi

ZIP/Postal Code

39232

Country

United States

Facility Name

City

Toms River

State/Province

New Jersey

ZIP/Postal Code

08755

Country

United States

Facility Name

City

Staten Island

State/Province

New York

ZIP/Postal Code

10312

Country

United States

Facility Name

City

Hickory

State/Province

North Carolina

ZIP/Postal Code

28601

Country

United States

Facility Name

City

Portland

State/Province

Oregon

ZIP/Postal Code

97210

Country

United States

Facility Name

City

Norristown

State/Province

Pennsylvania

ZIP/Postal Code

19401

Country

United States

Facility Name

City

Austin

State/Province

Texas

ZIP/Postal Code

78757

Country

United States

Facility Name

City

Bennington

State/Province

Vermont

ZIP/Postal Code

05201

Country

United States

Facility Name

City

Waukesha

State/Province

Wisconsin

ZIP/Postal Code

53188

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

23257314

Citation

Trzepacz PT, Cummings J, Konechnik T, Forrester TD, Chang C, Dennehy EB, Willis BA, Shuler C, Tabas LB, Lyketsos C. Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease. Int Psychogeriatr. 2013 May;25(5):707-19. doi: 10.1017/S1041610212002141. Epub 2012 Dec 21.

Results Reference

derived

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

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