Efficacy, Safety and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deuterated [d6]-Dextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

Participants with agitation secondary to dementia of the Alzheimer's type. The diagnosis of probable Alzheimer's disease (AD) was to be based on the "2011 Diagnostic Guidelines for Alzheimer's Disease" issued by the National Institute on Aging (NIA)-Alzheimer's Association (AA) workgroups.

Study Overview

• Status: Completed
• Conditions: Agitation in Patients With Dementia of the Alzheimer's Type
• Intervention / Treatment: Drug: Placebo; Drug: AVP-786

Detailed Description

Eligible participants for this study must have had a diagnosis of probable AD and must have had clinically meaningful agitation secondary to AD.

This was to be a multicenter, randomized, placebo-controlled study, consisting of 12 weeks of treatment.

Approximately 380 participants were to be enrolled at approximately 60 centers in North America.

Study medication was to be administered orally twice-daily from Day 1 through Day 85. Screening was to occur within approximately 4 weeks prior to randomization. Following screening procedures for assessment of inclusion and exclusion criteria, eligible participants were to be randomized into the study.

• Study Type: Interventional
• Enrollment (Actual): 387
• Phase: Phase 3

Contacts and Locations

Study Locations

• Estonia
  • Tallinn, Estonia, 11315
    • Clinical Research Site#1
  • Tallinn, Estonia, 11315
    • Clinical Research Site#2
  • Tartu, Estonia, 50406
    • Clinical Research Site
• Germany
  • Mittweida, Germany, 9648
    • Clinical Research Site
• Poland
  • Bydgoszcz, Poland, 85-163
    • Clinical Research Site
  • Kielce, Poland, 25-411
    • Clinical Research Site
  • Lublin, Poland, 20-064
    • Clinical Research Site
  • Poznan, Poland, 60-369
    • Clinical Research Site
  • Poznan, Poland, 61-853
    • Clinical Research Site
  • Pruszcz Gdanski, Poland, 83-000
    • Clinical Research Site
  • Siemianowice Śląskie, Poland, 41-100
    • Clinical Research Site
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-093
      • Clinical Research Site
• Portugal
  • Torres Vedras, Portugal, 2560-280
    • Clinical Research Site
• Puerto Rico
  • Bayamon, Puerto Rico, 961
    • Clinical Research Site
  • San Juan, Puerto Rico, 918
    • Clinical Research Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • Clinical Research Site
    • Scottsdale, Arizona, United States, 85254
      • Clinical Research Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72209
      • Clinical Research Site
  • California
    • Irvine, California, United States, 92697
      • Clinical Research Site#1
    • Irvine, California, United States, 92697
      • Clinical Research Site#2
    • Long Beach, California, United States, 90806
      • Clinical Research Site
    • Oceanside, California, United States, 92056
      • Clinical Research Site
    • Orange, California, United States, 92868
      • Clinical Research Site
    • San Diego, California, United States, 92103
      • Clinical Research Site#1
    • San Diego, California, United States, 92103
      • Clinical Research Site#2
    • Santa Ana, California, United States, 92704
      • Clinical Research Site
    • Tustin, California, United States, 92780
      • Clinical Research Site
  • Colorado
    • Denver, Colorado, United States, 80209
      • Clinical Research Site
  • Connecticut
    • Cromwell, Connecticut, United States, 06416
      • Clinical Research Site
    • New London, Connecticut, United States, 06320
      • Clinical Research Site
    • Norwalk, Connecticut, United States, 06851
      • Clinical Research Site
  • Florida
    • Atlantis, Florida, United States, 33462
      • Clinical Research Site
    • Boca Raton, Florida, United States, 33428
      • Clinical Research Site
    • Brandon, Florida, United States, 33511
      • Clinical Research Site
    • Coral Gables, Florida, United States, 33134
      • Clinical Research Site#1
    • Coral Gables, Florida, United States, 33134
      • Clinical Research Site#2
    • Coral Gables, Florida, United States, 33134
      • Clinical Research Site#3
    • Deerfield Beach, Florida, United States, 33064
      • Clinical Research Site#1
    • Doral, Florida, United States, 33166
      • Clinical Research Site
    • Hialeah, Florida, United States, 33012
      • Clinical Research Site
    • Hialeah, Florida, United States, 33016
      • Clinical Research Site#1
    • Hialeah, Florida, United States, 33016
      • Clinical Research Site#2
    • Jacksonville, Florida, United States, 32256
      • Clinical Research Site
    • Kendall, Florida, United States, 33175
      • Clinical Research Site
    • Kissimmee, Florida, United States, 34741
      • Clinical Research Site
    • Kissimmee, Florida, United States, 34744
      • Clinical Research Site
    • Lake Worth, Florida, United States, 33449
      • Clinical Research Site
    • Miami, Florida, United States, 33122
      • Clinical Research Site
    • Miami, Florida, United States, 33175
      • Clinical Research Site
    • Miami, Florida, United States, 33125
      • Clinical Research Site#1
    • Miami, Florida, United States, 33125
      • Clinical Research Site#2
    • Miami, Florida, United States, 33126
      • Clinical Research Site
    • Miami, Florida, United States, 33133
      • Clinical Research Site
    • Miami, Florida, United States, 33135
      • Clinical Research Site#1
    • Miami, Florida, United States, 33135
      • Clinical Research Site#2
    • Miami, Florida, United States, 33136
      • Clinical Research Site
    • Miami, Florida, United States, 33137
      • Clinical Research Site
    • Miami, Florida, United States, 33144
      • Clinical Research Site
    • Miami, Florida, United States, 33145
      • Clinical Research Site
    • Miami, Florida, United States, 33165
      • Clinical Research Site
    • Miami, Florida, United States, 33176
      • Clinical Research Site#2
    • Miami, Florida, United States, 33183
      • Clinical Research Site
    • Miami, Florida, United States, 33467
      • Clinical Research Site
    • Naples, Florida, United States, 34102
      • Clinical Research Site
    • Oakland Park, Florida, United States, 33334
      • Clinical Research Site
    • Orlando, Florida, United States, 32819
      • Clinical Research Site
    • Ormond Beach, Florida, United States, 32174
      • Clinical Research Site
    • Palm Beach Gardens, Florida, United States, 33410
      • Clinical Research Site
    • Palmetto Bay, Florida, United States, 33157
      • Clinical Research Site
    • Pompano Beach, Florida, United States, 33064
      • Clinical Research Site#2
    • Saint Petersburg, Florida, United States, 33713
      • Clinical Research Site
    • Sarasota, Florida, United States, 34243
      • Clinical Research Site
    • Tampa, Florida, United States, 33634
      • Clinical Research Site
    • Tampa, Florida, United States, 33609
      • Clinical Research Site#1
    • Tampa, Florida, United States, 33609
      • Clinical Research Site#2
    • Tampa, Florida, United States, 33613
      • Clinical Research Site#2
    • The Villages, Florida, United States, 32162
      • Clinical Research Site
    • West Palm Beach, Florida, United States, 33407
      • Clinical Research Site
    • Winter Park, Florida, United States, 32789
      • Clinical Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Clinical Research Site
    • Newnan, Georgia, United States, 30265
      • Clinical Research Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Clinical Research Site
  • Illinois
    • Schaumburg, Illinois, United States, 60194
      • Clinical Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Clinical Research Site
  • Kansas
    • Lenexa, Kansas, United States, 66214
      • Clinical Research Site
  • Kentucky
    • Paducah, Kentucky, United States, 42003
      • Clinical Research Site
  • Massachusetts
    • Bedford, Massachusetts, United States, 01730
      • Clinical Research Site
    • Quincy, Massachusetts, United States, 02169
      • Clinical Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Clinical Research Site
    • Paw Paw, Michigan, United States, 49079
      • Clinical Research Site
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Clinical Research Site
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Clinical Research Site
    • Saint Louis, Missouri, United States, 63128
      • Clinical Research Site
  • New Jersey
    • Mount Arlington, New Jersey, United States, 07856
      • Clinical Research Site
    • Toms River, New Jersey, United States, 08755
      • Clinical Research Site
    • West Long Branch, New Jersey, United States, 07764
      • Clinical Research Site
  • New York
    • Amherst, New York, United States, 14226
      • Clinical Research Site
    • Brooklyn, New York, United States, 11229
      • Clinical Research Site
    • New York, New York, United States, 10036
      • Clinical Research Site
    • New York, New York, United States, 10032
      • Clinical Research Site
    • Orangeburg, New York, United States, 10962
      • Clinical Research Site
    • Rochester, New York, United States, 14620
      • Clinical Research Site
    • Staten Island, New York, United States, 10312
      • Clinical Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Clinical Research Site
    • Winston-Salem, North Carolina, United States, 27157
      • Clinical Research Site
  • Ohio
    • Akron, Ohio, United States, 44320
      • Clinical Research Site
    • Cincinnati, Ohio, United States, 45219
      • Clinical Research Site
    • Columbus, Ohio, United States, 43210
      • Clinical Research Site#1
    • Columbus, Ohio, United States, 43210
      • Clinical Research Site#2
    • Dayton, Ohio, United States, 45459
      • Clinical Research Site
    • Westerville, Ohio, United States, 43082
      • Clinical Research Site
  • Oklahoma
    • Edmond, Oklahoma, United States, 73012
      • Clinical Research Site
    • Oklahoma City, Oklahoma, United States, 73106
      • Clinical Research Site
    • Oklahoma City, Oklahoma, United States, 73112
      • Clinical Research Site
    • Oklahoma City, Oklahoma, United States, 73103
      • Clinical Research Site
  • Pennsylvania
    • Moosic, Pennsylvania, United States, 18507
      • Clinical Research Site
    • Willow Grove, Pennsylvania, United States, 19090
      • Clinical Research Site
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Clinical Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Clinical Research Site
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Clinical Research Site#2
  • Texas
    • Dallas, Texas, United States, 75231
      • Clinical Research Site
    • Dallas, Texas, United States, 75390-8898
      • Clinical Research Site
    • Irving, Texas, United States, 75062
      • Clinical Research Site
    • Mansfield, Texas, United States, 76063
      • Clinical Research Site
  • Utah
    • Clinton, Utah, United States, 84015
      • Clinical Research Site
  • Vermont
    • Woodstock, Vermont, United States, 05091
      • Clinical Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of probable Alzheimer's Disease (AD) according to the 2011 National Institute on Aging-Alzheimer's Association (NIA-AA) working groups criteria
• The participant has clinically significant, moderate/severe agitation at the time of screening and for at least 2 weeks prior to randomization
• The diagnosis of agitation must meet the International Psychogeriatric Association (IPA) provisional definition of agitation
• Either out patients or residents of an assisted-living facility or a skilled nursing home
• Clinical Global Impression of Severity of Illness (CGIS) score assessing Agitation is >= 4 (moderately ill) at screening and baseline
• Mini-Mental State Examination (MMSE) score is between 6 and 26 (inclusive) at screening and baseline
• Caregiver who is able and willing to comply with all required study procedures. In order to qualify as a reliable informant (i.e., caregiver) capable of assessing changes in participant's condition during the study, the individual must spend a minimum of 2 hours per day for 4 days per week with the participant.

Exclusion Criteria:

• Participant has dementia predominantly of non-Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia)
• Participants with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g., malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease)
• Participant with myasthenia gravis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Stage 1: Placebo; Participants received matching placebo orally twice daily (BID) for 6 weeks (Days 1-42) in Stage 1. Participants who completed Stage 1 were eligible to Participate in Stage 2.	Drug: Placebo
EXPERIMENTAL: Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg); Participants received AVP-786-18 mg orally once daily (QD) in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for the remaining 5 weeks (Days 8-42). Participants who completed Stage 1 were eligible to participate in Stage 2.	Drug: AVP-786
EXPERIMENTAL: Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg); Participants received AVP-786-18 mg orally QD in the morning and placebo orally QD in the evening for the first 7 days, followed by AVP-786-18 mg orally BID for 2 weeks (Days 8-21). From Day 22, participants received AVP-786-28 mg orally BID for the remaining 3 weeks. Participants who completed Stage 1 were eligible to participate in Stage 2.	Drug: AVP-786
PLACEBO_COMPARATOR: Stage 2: Placebo; Participants who received matching placebo orally BID for 6 consecutive weeks in Stage 1 were re-randomized in Stage 2 to receive the study drug or placebo from Day 43 to Day 85.	Drug: Placebo
EXPERIMENTAL: Stage 1: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) to: Stage 2: AVP-786-18 (d6-DM 18 mg/Q 4.9 mg); Participants who received AVP-786-18 mg in Stage 1 continued to receive AVP-786-18 mg orally BID for the 6 weeks (Days 43-85) in Stage 2..	Drug: Placebo; Drug: AVP-786
EXPERIMENTAL: Stage 1: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) to Stage 2: AVP-786-28 (d6-DM 28 mg/Q 4.9 mg); Participants who received AVP-786-28 mg in Stage 1 continued to receive AVP-786-28 mg orally BID for 6 weeks (Days 43-85) in Stage 2	Drug: Placebo; Drug: AVP-786
EXPERIMENTAL: Experimental: Stage 1: Placebo to: Stage 2: AVP-786-18 d6-DM 18 mg/Q 4.9 mg; Participants who were placebo responders or non-responders in Stage 1 received AVP-786-18 for 1 week, orally, QD, followed by AVP-786-18 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks.	Drug: Placebo; Drug: AVP-786
EXPERIMENTAL: Stage 1: Placebo to: Stage 2: AVP-786-28 d6 DM 28 mg/Q 4.9 mg; Participants who were placebo responders or non-responders in Stage 1 received AVP-786-28 for 1 week, orally, QD, followed by AVP-786-28 BID for 2 weeks; followed by AVP-786-28 BID for the last 3 weeks.	Drug: Placebo; Drug: AVP-786

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1 and Stage 2: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score to Week 6 and Week 12	The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency: 1, never; 2, less than once a week; 3, once or twice a week; 4, several times a week; 5, once or twice a day; 6, several times a day; 7, several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Least Squares Mean Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC)-Agitation Score at Week 6 and Week 12	The intent of the ADCS version of the CGIC is to provide a means to reliably assess the global impression of change from Baseline in a clinical trial. The mADCS-CGIC is a modification of the ADCS-CGIC instrument that focuses specifically on agitation. The participants are asked to rate their impression of change from Baseline as: 1, marked improvement; 2, moderate improvement; 3, minimal improvement; 4, no change; 5, minimal worsening; 6, moderate worsening; 7, marked worsening. Baseline was defined as the last non-missing assessment prior to Stage 1 randomization. Treatment effects were estimated at each stage by analysis of covariance (ANCOVA) with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus [vs] > 6), risk assessments for falls (normal/mild vs moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by last observation carried forward (LOCF) within each stage.	Stage 1 Week 6; Stage 2 Week 12
Stage 1 and Stage 2: Change From Baseline in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score to Week 6 and Week 12	The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. The Agitation/Aggression domain is designed to collect information on the behavioral aspects of agitation/aggression in participants with probable Alzheimer's Disease (AD) and clinically meaningful agitation secondary to AD. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the NPI Caregiver Distress Score to Week 6 and Week 12	The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate caregiver distress. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, marked severe. The total caregiver distress score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the NPI Aberrant Motor Behavior Domain Score to Week 6 and Week 12	The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate aberrant motor behavior. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening of the symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the Zarit Burden Interview (ZBI) Score to Week 6 and Week 12	The ZBI is a 22-item scale used to assess the impact of a participant with dementia and also other illnesses on the caregiver's burden. For each item of the scale, the caregiver indicates how often they feel the burden (never, rarely, sometimes, quite frequently, or nearly always). The score ranges from 0 to 88 and is determined by adding the numbered responses of the individual items. Higher scores indicate greater caregiver distress. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the NPI Irritability/Lability Domain Score to Week 6 and Week 12	The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains, including the irritability/lability domain score. Each NPI domain is rated by the caregiver for symptom frequency and severity. Symptom frequency is rated as: 1, occasionally; 2, often; 3, frequently; 4, very frequently. Symptom severity is rated as: 1, mild; 2, moderate; 3, severe. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. Higher scores indicate worsening of the symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the NPI Total Score to Week 6 and Week 12	NPI evaluates both frequency and severity of 12 neuropsychiatric disturbances including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, as well as appetite/eating. Total domain score= frequency x severity and thus ranges from 1 to 12. NPI domain is rated by caregiver for symptom frequency and severity. Frequency is rated as: 1=occasionally, 2=often, 3= frequently, and 4=very frequently. Severity is rated as: 1=mild; 2= moderate, and 3=severe. Frequency and severity rating scales has defined anchor points to enhance reliability of caregiver responses. Caregiver distress is rated for each positive neuropsychiatric symptom using following anchored scores. It is rated as 0=not at all, 1=minimal, 3=moderate, 4=severe, 5=very severe. Total score is calculated by adding the individual Item scores, to yield a possible total scores of 0 to 144.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score to Week 6 and Week 12	The CGIS-Agitation is an observer-rated scale that measures illness severity. CGIS is used to assess the severity of agitation. The CGIS score is rated on a 7-point scale (1 = normal, not at all ill; 7 = among the most extremely ill participants). Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Rating at Week 6 and Week 12	The ADCS-CGIC rating scale provides a reliable means to assess change from a Baseline level of global function within the time frame of the trial. ADCS-CGIC-Overall focuses on the clinician's observations of change in the participant's cognitive, functional, and behavioral performance. The ADCS-CGIC-Overall responses (1-7) are rated as: 1 = marked improvement, 2 = moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, or 7 = marked worsening. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes versus no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Patient Global Impression of Change (PGIC) Score at Week 6 and Week 12	The PGIC is a 7-point (1-7) scale used to assess treatment response: 1 = very much improved, = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, or 7 = very much worse. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline CMAI Total score, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score to Week 6 and Week 12	The DEMQOL scale is used to evaluate health-related QOL in participants with dementia and their caregivers. There are 2 versions of the DEMQOL: a 28-item version (rated by the participant); and a 31-item version (DEMQOL-proxy, rated by the caregiver). Both versions are recommended for evaluating participants (and their caregivers) with mild to moderate dementia. The DEMQOL total score ranges from 28 to 112. The DEMQOL-proxy is used for participants with severe dementia; the total score ranges from 31 to 124. For both versions, higher scores indicate greater QOL. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 vs > 6), risk assessments for falls (normal/mild vs moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1 and Stage 2: Change From Baseline in the Cornell Scale for Depression in Dementia (CSDD) Score to Week 6 and Week 12	The CSDD scale is used to assess signs/symptoms of major depression in participants with dementia. CSDD has 19 items, and each item is rated for severity on the following scale of 0 to 2 (0 =absent, 1= mild/intermittent 2=severe). CSDD score is calculated by summing non-missing scores from each item score. The scale ranges from 0-no depression to 38 maximum depressions. Scores above 10 indicate a probable major depression, above 18 indicate a definite major depression, and below 6 as a rule are associated with the absence of significant depressive symptoms. Higher score indicated maximum depression.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 2: Percentage of Participants With General Medical Health Rating (GMHR) Score	The GMHR is a global clinical rating for medical health, designed to quantify in a single number (1 to 4) the severity of general comorbidity in a participant with dementia. The ratings are: 1 = poor; 2 = fair; 3 = good; 4 = excellent to very good. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.	Baseline; Week 12
Stage 1 and Stage 2: Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score to Week 6 and Week 12	The ADAS is designed to evaluate the cognitive and non-cognitive behavioral dysfunction characteristics of participants with AD. The cognitive subscale (ADAS-cog) consists of 11 subsets related to memory, praxis, and language. ADAS-cog scores range from 0 to 70. Higher scores indicate greater cognitive impairment. The ADAS-cog is assessed for participants with an Mini-Mental State Examination (MMSE) score of ≥10 at the Baseline Visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Treatment effects were estimated at each stage by ANCOVA with fixed effects for treatment, Baseline, and in the Stage 1 model, Baseline NPI AA (≤ 6 versus > 6), risk assessments for falls (normal/mild versus moderate/severe), Baseline concomitant use of antipsychotic medications (yes vs no). Missing values were imputed by LOCF within each stage.	Stage 1: Baseline, Week 6; Stage 2: Baseline (Week 6), Week 12
Stage 1: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals	RUD evaluates dementia participants utilization of formal and informal healthcare resources, including hospitalizations and doctor visits, living assistance, and time spent by nonprofessional caregivers. The RUD is administered as a semi-structured interview with the participant's primary caregiver and contains 2 sections; one focusing on caregiver impact (loss of work and leisure time incurred by caregiver) and the other focusing on the participant's use of healthcare resources. Information of caregivers who reported their responsibilities affected their work and who visited healthcare professionals from the interviews during Stage 1 is reported for this outcome measure. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.	Stage 1: Week 6
Stage 2: Resource Utilization in Dementia (RUD): Percentage of Caregiver Who Reported That Their Responsibilities Affected Their Work and Who Visited Health Care Professionals	RUD evaluates dementia participants utilization of formal and informal healthcare resources, including hospitalizations and doctor visits, living assistance, and time spent by nonprofessional caregivers. The RUD is administered as a semi-structured interview with the participant's primary caregiver and contains 2 sections; one focusing on caregiver impact (loss of work and leisure time incurred by caregiver) and the other focusing on the participant's use of healthcare resources. Information of caregivers who reported their responsibilities affected their work and who visited healthcare professionals from the interviews during Stage 2 is reported for this outcome measure. Data was collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.	Stage 2: Week 12
Stage 1: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant	RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on hours per day caregiver spent assisting participant from interviews during Stage 1 is reported for this outcome measure, where the following questions (Q), Q1= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as toilet visits, eating, dressing, grooming, walking, bathing? Q2= On typical care day during the last 30 days, how much time per day did you assist participant with tasks as (shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= On typical care day during last 30 days, how much time per day did you spend supervising (preventing dangerous events)?(Q3). Data is collected for treatment arm groups as pre-specified in protocol for this outcome measure.	Stage 1: Week 6
Stage 2: Resource Utilization in Dementia (RUD): Number of Hours Per Day the Caregiver Spent Assisting the Participant	RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on hours per day caregiver spent assisting participant from interviews during Stage 1 is reported for this outcome measure, where the following questions (Q), Q1= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as toilet visits, eating, dressing, grooming, walking, bathing? Q2= On typical care day during the last 30 days, how much time per day did you assist participant with tasks as (shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= On typical care day during last 30 days, how much time per day did you spend supervising (preventing dangerous events)?(Q3). Data is collected for treatment arm groups as pre-specified in protocol for this outcome measure.	Stage 2: Week 12
Stage 1: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant	RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on days caregiver spent assisting participant from interviews during Stage 1 is reported for outcome measure, where following questions (Q), Q1= During last 30 days, how many days did you spend providing these (toilet visits, eating, dressing, grooming, walking, bathing) services to participant?; Q2= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= During last 30 days, how many days did you spend providing these services (supervising) to the participant?. Data is collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.	Stage 1: Week 6
12-Week Parallel Group: Resource Utilization in Dementia (RUD) Score: Number of Days the Caregiver Spent Assisting the Participant	RUD evaluates dementia participants utilization of formal, informal healthcare resources, including hospitalizations, doctor visits, living assistance, time spent by nonprofessional caregivers. Information on days caregiver spent assisting participant from interviews during Stage 1 is reported for outcome measure, where following questions (Q), Q1= During last 30 days, how many days did you spend providing these (toilet visits, eating, dressing, grooming, walking, bathing) services to participant?; Q2= On typical care day during last 30 days, how much time per day did you assist participant with tasks such as shopping, food preparation, housekeeping, laundry, transportation, taking medication, managing financial matters?; Q3= During last 30 days, how many days did you spend providing these services (supervising) to the participant?. Data is collected for the treatment arm groups as pre-specified in the protocol for this outcome measure.	12-Week Parallel Group: Week 12

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 23, 2015
• Primary Completion (ACTUAL): January 30, 2019
• Study Completion (ACTUAL): February 27, 2019

Study Registration Dates

• First Submitted: May 11, 2015
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (ESTIMATE): May 13, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Dementia; Agitation
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; Dyskinesias; Psychomotor Disorders; Tauopathies; Psychomotor Agitation; Dementia; Alzheimer Disease
• Other Study ID Numbers: 15-AVP-786-301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No