Agitation in Patients With Dementia of the Alzheimer's Type
Conditions
Keywords
Agitation, Dementia of the Alzheimer's type, Alzheimer's disease, AVP-786, Deudextromethorphan hydrobromide, Quinidine sulfate
Brief summary
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.
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.
Interventions
DRUGAVP-786
oral capsules
DRUGPlacebo
oral capsules
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From the End of Period A (Week 1) to Week 10 in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score | Week 1 to Week 10 | 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. |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | From randomization (Week 2) up to 30 days after last dose of study drug (Up to Week 16) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Week 1 to Week 10 | 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. |
Countries
Bulgaria, Denmark, Estonia, Germany, Greece, Poland, Portugal, Puerto Rico, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at clinical sites in the North America and Europe from 13 July 2020 to 27 June 2024.
Pre-assignment details
A total of 530 participants were screened for the study, of which 184 participants were enrolled and treated with placebo in a 1-week double-blind placebo lead-in period (Period A). A total of 173 participants were then randomized to receive AVP-786 (deudextromethorphan hydrobromide \[d6-DM\]/quinidine sulfate \[Q\])-18, AVP-786-42.63 or placebo in the 11-week randomization period (Period B).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were enrolled in 1-week double-blind placebo lead-in Period A, and were then randomized to receive AVP-786 matching placebo capsules, twice a day, for 11 weeks in Period B. | 56 |
| AVP-786-18 Participants were enrolled in 1-week double-blind placebo lead-in Period A, and were then randomized to receive AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) capsules, twice a day, for 11 weeks in Period B. | 60 |
| AVP-786-42.63 Participants were enrolled in 1-week double-blind placebo lead-in Period A, and 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. | 57 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period A (Placebo lead-in) | Other | 11 | 0 | 0 | 0 |
| Period B (Randomization Period) | Adverse Event | 0 | 3 | 0 | 1 |
| Period B (Randomization Period) | Death | 0 | 0 | 1 | 0 |
| Period B (Randomization Period) | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Period B (Randomization Period) | Physician Decision | 0 | 0 | 1 | 0 |
| Period B (Randomization Period) | Protocol Deviation | 0 | 1 | 0 | 0 |
| Period B (Randomization Period) | Reason not Specified | 0 | 1 | 0 | 2 |
| Period B (Randomization Period) | Study Subject Withdrawal by Parent or Guardian | 0 | 2 | 2 | 2 |
| Period B (Randomization Period) | Study Terminated by Sponsor | 0 | 1 | 5 | 3 |
| Period B (Randomization Period) | Withdrawal by Subject | 0 | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | AVP-786-42.63 | AVP-786-18 | Placebo |
|---|---|---|---|---|
| Age, Continuous | 75.0 years STANDARD_DEVIATION 7.35 | 74.8 years STANDARD_DEVIATION 6.47 | 73.9 years STANDARD_DEVIATION 7.85 | 76.5 years STANDARD_DEVIATION 7.52 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 107 Participants | 36 Participants | 39 Participants | 32 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 61 Participants | 20 Participants | 19 Participants | 22 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 4 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 158 Participants | 53 Participants | 55 Participants | 50 Participants |
| Sex: Female, Male Female | 111 Participants | 33 Participants | 42 Participants | 36 Participants |
| Sex: Female, Male Male | 62 Participants | 24 Participants | 18 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 1 / 60 | 0 / 57 |
| other Total, other adverse events | 20 / 56 | 14 / 60 | 17 / 57 |
| serious Total, serious adverse events | 1 / 56 | 3 / 60 | 2 / 57 |
Outcome results
Primary
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.
Time frame: Week 1 to Week 10
Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified primary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.
Primary
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.
Time frame: From randomization (Week 2) up to 30 days after last dose of study drug (Up to Week 16)
Population: Safety population included of all participants who were randomized in the double-blind period B of this study, and took at least one dose of double-blind, randomized study medication. As pre-specified in the Statistical Analysis Plan (SAP), safety data was planned to be collected only for the participants who were randomized in the double-blind period B of this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | TEAEs | 20 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | Serious TEAEs | 1 Participants |
| AVP-786-18 | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | TEAEs | 15 Participants |
| AVP-786-18 | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | Serious TEAEs | 3 Participants |
| AVP-786-42.63 | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | TEAEs | 17 Participants |
| AVP-786-42.63 | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Serious TEAE | Serious TEAEs | 2 Participants |
Secondary
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.
Time frame: Week 1 to Week 10
Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.