Assessment of the 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 (Deudextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

This study was conducted to evaluate the efficacy, safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) compared to placebo for the treatment of agitation in participants with dementia of the Alzheimer's type.

Study Overview

• Status: Terminated
• 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 had a diagnosis of probable Alzheimer's disease (AD) and had clinically significant, moderate/severe agitation secondary to AD.

This was a multicenter, randomized, double-blind, placebo-controlled study, consisting of 12 weeks of treatment. Screening occurred within 4 weeks prior to randomization. Following screening procedures for assessment of inclusion and exclusion criteria, eligible participants were randomized into the study.

184 participants were enrolled into the study.

Study medication was administered orally twice daily from Day 1 through Day 85.

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Pernik, Bulgaria, 2300
    • Clinical Research Site #100-115
  • Pleven, Bulgaria, 5800
    • Clinical Research Site #100-112
  • Plovdiv, Bulgaria, 4002
    • Clinical Research Site #100-106
  • Sofia, Bulgaria, 1408
    • Clinical Research Site #100-102
  • Sofia, Bulgaria, 1408
    • Clinical Research Site #100-111
  • Varna, Bulgaria, 9020
    • Clinical Research Site #100-105
  • Varna, Bulgaria, 9020
    • Clinical Research Site #100-108
  • Veliko Tarnovo, Bulgaria, 5006
    • Clinical Research Site #100-113
• Denmark
  • Aalborg, Denmark, 9000
    • Clinical Research Site #208-002
  • Region Nordjylland
    • Aalborg, Region Nordjylland, Denmark, 9000
      • Clinical Research Site # 208-001
• Estonia
  • Tallinn, Estonia, 11315
    • Clinical Research Site #1 Site #233-002
  • Tallinn, Estonia, 11315
    • Clinical Research Site #2 Site #233-004
  • Tartu, Estonia, 50406
    • Clinical Research Site #233-001
• Germany
  • Berlin, Germany, 13187
    • Clinical Research Site 276-014
  • Baden-Württemberg
    • Böblingen, Baden-Württemberg, Germany, 71034
      • Clinical Research Site #276-017
  • Hessen
    • Bad Homburg Vor Der Höhe, Hessen, Germany, 61348
      • Clinical Research Site #276-005
  • Thüringen
    • Gera, Thüringen, Germany, 935
      • Clinical Research Site #276-012
• Greece
  • Athens, Greece, 15125
    • Clinical Research Site# 300-005
  • Ioannina, Greece, 45500
    • Clinical Research Site #300-006
  • Thessaloníki, Greece, 54645
    • Clinical Research Site #300-003
• Poland
  • Bydgoszcz, Poland, 85-163
    • Clinical Research Site #616-013
  • Kielce, Poland, 25-411
    • Clinical Research Site #616-004
  • Lublin, Poland, 20-064
    • Clinical Research Site #616-008
  • Lublin, Poland, 20-080
    • Clinical Research Site #616-010
  • Poznan, Poland, 60-369
    • Clinical Research Site #616-012
  • Poznan, Poland, 61-853
    • Clinical Research Site #616-005
  • Pruszcz Gdanski, Poland, 83-000
    • Clinical Research Site #616-001
  • Warszawa, Poland, 01-737
    • Clinical Research Site #616-007
  • Katowice
    • Zabrze, Katowice, Poland, 41-807
      • Clinical Research Site #616-018
  • Kujawsko-Pomorskie
    • Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-023
      • Clinical Research Site #616-009
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-093
      • Clinical Research Site #616-006
  • Mazowieckie
    • Sochaczew, Mazowieckie, Poland, 96-500
      • Clinical Research Site #616-015
• Portugal
  • Braga, Portugal, 4710-243
    • Clinical Research Site #620-004
  • Coimbra, Portugal, 3000-075
    • Clinical Research Site #620-005
  • Torres Vedras, Portugal, 2560-280
    • Clinical Research Site #620-002
  • Braga
    • Guimarães, Braga, Portugal, 4835-044
      • Clinical Research Site #620-007
• Puerto Rico
  • Bayamon, Puerto Rico, 00961
    • Clinical Research Site #630-001
  • Rio Piedras, Puerto Rico, 00935
    • Clinical Research Site #630-003
  • San Juan, Puerto Rico, 00918
    • Clinical Research Site #630-002
  • San Juan, Puerto Rico, 926
    • Clinical Research Site #630-005
• Ukraine
  • Dnipro, Ukraine, 49005
    • Clinical Research Site #804-006
  • Kharkiv, Ukraine, 61068
    • Clinical Research Site #804-003
  • Kiev, Ukraine, 8631
    • Clinical Research Site #804-004
  • Kyiv, Ukraine, 04080
    • Clinical Research Site #804-005
  • Lviv, Ukraine, 79021
    • Clinical Research Site #804-007
• United Kingdom
  • Blandford Forum, United Kingdom, DT11 7DD
    • Clinical Research Site #826-003
  • Crowborough, United Kingdom, TN61NY
    • Clinical Research Site #826-004
  • Fulwood, United Kingdom, PR2 9HT
    • Clinical Research Site #826-001
  • Manchester, United Kingdom, M25 3BL
    • Clinical Research Site# 826-006
  • Motherwell, United Kingdom, ML1 4UF
    • Clinical Research Site #826-002
• United States
  • Arkansas
    • Fort Smith, Arkansas, United States, 72901
      • Clinical Research Site #840-081
  • California
    • La Jolla, California, United States, 92093
      • Clinical Research Site #840-035
    • Los Angeles, California, United States, 70072
      • Clinical Research Site #840-084
    • Oceanside, California, United States, 92056
      • Clinical Research Site #840-050
    • Pasadena, California, United States, 91105
      • Clinical Research Site #840-064
    • Santa Ana, California, United States, 92705
      • Clinical Research Site #840-098
  • Colorado
    • Basalt, Colorado, United States, 81621
      • Clinical Research Site #840-090
  • Florida
    • Atlantis, Florida, United States, 33462
      • Clinical Research Site #840-009
    • Brandon, Florida, United States, 33511
      • Clinical Research Site #840-056
    • Coral Gables, Florida, United States, 33134
      • Clinical Research Site #840-020
    • Doral, Florida, United States, 33166
      • Clinical Research Site #840-059
    • Hialeah, Florida, United States, 33012
      • Clinical Research Site #840-131
    • Jacksonville, Florida, United States, 32256
      • Clinical Research Site #840-039
    • Kissimmee, Florida, United States, 34744
      • Clinical Research Site #840-012
    • Maitland, Florida, United States, 32751
      • Clinical Research Site #840-069
    • Maitland, Florida, United States, 32751
      • Clinical Research Site #840-083
    • Miami, Florida, United States, 33032
      • Clinical Research Site #840-118
    • Miami, Florida, United States, 33126
      • Clinical Research Site #840-004
    • Miami, Florida, United States, 33126
      • Clinical Research Site #840-125
    • Miami, Florida, United States, 33144
      • Clinical Research Site #840-104
    • Miami, Florida, United States, 33165
      • Clinical Research Site #840-133
    • Miami, Florida, United States, 33175
      • Clinical Research Site #840-042
    • Miami, Florida, United States, 33467
      • Clinical Research Site #840-003
    • Orlando, Florida, United States, 32819
      • Clinical Research Site #840-036
    • Pembroke Pines, Florida, United States, 33024
      • Clinical Research Site 840-111
    • Pensacola, Florida, United States, 32503
      • Clinical Research Site #840-096
    • Pompano Beach, Florida, United States, 33064
      • Clinical Research Site
    • Tampa, Florida, United States, 33614
      • Clinical Research Site #840-079
    • Tampa, Florida, United States, 33615
      • Clinical Research Site #840-112
    • Tampa, Florida, United States, 33634
      • Clinical Research Site #840-046
    • West Palm Beach, Florida, United States, 33407
      • Clinical Research Site #840-107
  • Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Clinical Research Site #840-049
  • Michigan
    • Rochester Hills, Michigan, United States, 48307
      • Clinical Research Site #840-093
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Clinical Research Site #840-015
  • New Jersey
    • West Long Branch, New Jersey, United States, 07764
      • Clinical Research Site #840-029
  • New York
    • Bronx, New York, United States, 10466
      • Clinical Research Site #840-097
    • New Windsor, New York, United States, 12553
      • Clinical Research Site #840-072
  • North Carolina
    • Monroe, North Carolina, United States, 28112
      • Clinical Research Site #840-095
  • Ohio
    • Canton, Ohio, United States, 44718
      • Clinical Research Site #840-060
    • Columbus, Ohio, United States, 43210
      • Clinical Research Site #840-028
  • Oklahoma
    • Edmond, Oklahoma, United States, 73012
      • Clinical Research Site #840-061
    • Tulsa, Oklahoma, United States, 74136
      • Clinical Research Site #840-099
  • Texas
    • McKinney, Texas, United States, 75069
      • Clinical Research Site #840-115
    • The Woodlands, Texas, United States, 77381
      • Clinical Research Site
  • Virginia
    • Richmond, Virginia, United States, 23236
      • Clinical Research Site #840-025

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with a diagnosis of probable Alzheimer's disease according to the 2011 Neuropsychiatric Inventory Agitation/Aggression (NPI-AA) working groups criteria
• Participants with clinically significant, moderate-to-severe agitation for at least 2 weeks prior to Screening that interferes with daily routine per the Investigator's judgment
• Participants who require pharmacotherapy for the treatment of agitation per the Investigator's judgment after an evaluation of reversible factors and a course of nonpharmacological interventions
• Diagnosis of agitation must meet the International Psychogeriatric Association (IPA) provisional definition of agitation.
• Participants meeting an additional predetermined blinded eligibility criterion, which will remain blinded to the clinical study site Investigators and staff
• Participants with a reliable caregiver who is able and willing to comply with all study procedures, including adherence to administering study drug and not administering any prohibited medications during the course of the study, and who spends a minimum of 2 hours per day for 4 days per week with the participant

Exclusion Criteria:

• Participants with dementia predominantly of the non-Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia)
• Participants with symptoms of agitation that are not secondary to Alzheimer's dementia (e.g., secondary to pain, other psychiatric disorder, or delirium)
• 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 [except skin basal-cell carcinoma], poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease)
• Participants with myasthenia gravis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786 matching placebo capsules, twice a day, for 11 weeks in Period B.	Drug: Placebo; oral capsules
Experimental: AVP-786-18; Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786-18 (d6-DM 18 milligrams (mg)/Q 4.9 mg) capsules, twice a day, for 11 weeks in Period B.	Drug: AVP-786; oral capsules
Experimental: AVP-786-42.63; Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786-42.63 (d6-DM 42.63 mg/Q 4.9 mg) capsules, twice a day, for 11 weeks in Period B.	Drug: AVP-786; oral capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From the End of Period A (Week 1) to Week 10 in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score	The CMAI is used to assess the frequency of manifestations of agitated behaviors in elderly persons. It consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. Each of the 29 items is rated on a 7-point scale of frequency (1 = never, 2 = less than once a week but still occurring, 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 ratings are based on the 2 weeks preceding assessment of the CMAI. Higher scores indicate higher frequency of agitated behaviours while lower scores indicate lower frequency of agitated behaviours.	Week 1 to Week 10
Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE	An adverse event (AE) is any untoward medical occurrence or unintended change (eg, physical, psychological, or behavioral), including inter-current illness, that does not necessarily have a causal relationship with the study treatment. A serious adverse event (SAE) is any AE occurring at any dose that results in death, life-threatening experience, persistent or significant disability/incapacity, in-patient hospitalization or prolongation of hospitalization or congenital anomaly/birth defect. TEAEs are all AEs (including serious and non-serious) which started after start of double-blind study drug treatment; or if the event was continuous from baseline and was worsening, serious, study drug related, or resulted in death, discontinuation, interruption or reduction of study therapy.	From randomization (Week 2) up to 30 days after last dose of study drug (Up to Week 16)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From the End of Period A (Week 1) to Week 10 in the Clinical Global Impression of Severity of Illness (CGIS) Score, as Related to Agitation	The CGIS is an observer-rated scale that measures illness severity. The CGIS-Agitation is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = among the most extremely ill patients) and assesses severity of agitation in this study. Higher scores indicate severe agitation while the lower scores indicate little or no agitation.	Week 1 to Week 10

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2020
• Primary Completion (Actual): June 27, 2024
• Study Completion (Actual): June 27, 2024

Study Registration Dates

• First Submitted: May 26, 2020
• First Submitted That Met QC Criteria: May 26, 2020
• First Posted (Actual): May 29, 2020

Study Record Updates

• Last Update Posted (Actual): May 30, 2025
• Last Update Submitted That Met QC Criteria: May 12, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Agitation; Dementia of the Alzheimer's type; AVP-786; Deudextromethorphan hydrobromide; Quinidine sulfate
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Behavioral Symptoms; Neurobehavioral Manifestations; Neurocognitive Disorders; Tauopathies; Neurodegenerative Diseases; Dyskinesias; Psychomotor Disorders; Alzheimer Disease; Dementia; Psychomotor Agitation
• Other Study ID Numbers: 20-AVP-786-306; 2020-000798-26 (EudraCT Number); 2023-504990-19-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

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