Efficacy, Safety and Tolerability Study of AVP-923 (Dextromethorphan/Quinidine) for Treatment of Symptoms of Agitation in Participants With Alzheimer's Disease

Study Overview
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Brief Summary
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The objectives of the study are to evaluate the safety, tolerability and efficacy of AVP-923 compared to placebo, for the treatment of symptoms of agitation in participants with Alzheimer's Disease (AD).

Detailed Description
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Eligible participants for this study must have a diagnosis of probable AD and must have clinically meaningful agitation secondary to AD. This is a multicenter, randomized, double-dummy, double-blind, placebo-controlled study, consisting of 10 weeks of treatment. Up to 200 participants will be enrolled at approximately 30-40 centers in the US. Study medication will be administered orally twice-daily from Day 1 through Day 70. Screening must occur within within approximately 4 weeks prior to randomization. Following screening procedures for assessment of inclusion and exclusion criteria, eligible participants will be randomized into the study.

Official Title
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A Phase 2, Randomized, Double-dummy, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety and Tolerability of AVP-923 (Dextromethorphan/Quinidine) for the Treatment of Symptoms of Agitation in Patients With Alzheimer's Disease.

Conditions
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Agitation, Alzheimer's Disease

Intervention / Treatment
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* Drug: AVP-923-20
* Drug: Placebo
* Drug: AVP-923-30


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of probable Alzheimer's disease (AD). The participant has clinically significant symptoms of agitation secondary to AD, that interfere with daily routine and for which a prescription medication is deemed indicated, in the opinion of the investigator. Either out-patients or residents of an assisted-living facility or a skilled nursing home. CGI-S score is ≥ 4 (moderately ill) at screening and baseline. Mini Mental State Examination (MMSE) score at screening between 8 and 28 (inclusive). Caregiver who is able and willing to comply with all required study procedures, ensuring that the participant attends all study visits and takes the study medication as instructed. In order to qualify as a caregiver for this study, the individual should spend time with the participant for a minimum of 4 hours on 4 separate days per week. Key Exclusion Criteria: Participant has other type of dementia (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia). Participant 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, certain cardiac conduction abnormalities including QTc prolongation, or unstable valvular heart disease). Participant with myasthenia gravis.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo during Stage 1 and Stage 2 of the study. | Drug: Placebo<br>* Placebo capsule<br>|
| Experimental: AVP-923<br>Participants will receive AVP-923-20 and AVP-923-30 in a sequential manner during Stage 1 and Stage 2 of the study. | Drug: AVP-923-20<br>* AVP-923-20: 20 mg of dextromethorphan and 10 mg of quinidine<br>* Other names: Nuedexta;Drug: AVP-923-30<br>* AVP-923-30: 30 mg of dextromethorphan and 10 mg of quinidine<br>|
| Experimental: Placebo then AVP-923<br>Participants will receive placebo in Stage 1 followed by AVP-923 in Stage 2. | Drug: AVP-923-20<br>* AVP-923-20: 20 mg of dextromethorphan and 10 mg of quinidine<br>* Other names: Nuedexta;Drug: Placebo<br>* Placebo capsule<br>Drug: AVP-923-30<br>* AVP-923-30: 30 mg of dextromethorphan and 10 mg of quinidine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | 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 was 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, marked. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. Data are reported for only those participants contributing data to the analysis. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Type of Adverse Event | Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred, or worsened, after the first dose of study medication and within 30 days after the permanent discontinuation of the study medication (first dose date ≤ AE start date ≤ date of last dose + 30 days) | up to Week 10 | 
| Change in the Total NPI Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The total score is calculated as a sum of all 12 domain scores and thus ranges from 12 to 144. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Individual NPI Domain Scores From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. Sleep/nighttime behavior disorders = S/NB disorders. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Sum of the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior NPI Domain (NPI4D) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The NPI4D score is the sum of the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior domain scores, and thus ranges from 4 to 48. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Sum of the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior NPI Domain (NPI4A) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and 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. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. The NPI4A score is the sum of the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior domain scores, and thus ranges from 4 to 48. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Total Neuropsychiatric Inventory-Caregiver Distress Score (NPI-CDS) From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. For each domain, the caregiver is asked to rate how emotionally distressing they find the symptom behavior on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The total NPI-CDS score is calculated as the sum of all 12 domain scores and thus ranges from 0 to 60. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the NPI-CDS for the Agitation/Aggression Domain From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. For the Agitation/Aggression domain, the caregiver is asked to rate how emotionally distressing they find the symptom behavior on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the NPI-CDS NPI4D Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. For the NPI4D NPI-CDS score, the caregiver is asked to rate how emotionally distressing they find the symptom behavior (for the Agitation/Aggression, Irritability/Lability, Disinhibition, and Aberrant Motor Behavior domains) on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The NPI4D NPI-CDS score ranges from 0 to 20. A higher score represents increased distress. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the NPI-CDS NPI4A Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The NPI is a retrospective interview covering 12 neuropsychiatric symptom domains and is used to evaluate psychopathology, neuropsychiatric manifestations, and caregiver distress. For the NPI4A NPI-CDS score, the caregiver is asked to rate how emotionally distressing they find the symptom behavior (for the Agitation/Aggression, Irritability/Lability, Anxiety, and Aberrant Motor Behavior domains) on the following scale: 0, not at all; 1, minimally; 2, mildly; 3, moderately; 4, severely; 5, very severely or extremely. The NPI4A NPI-CDS score ranges from 0 to 20. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Caregiver Strain Index (CSI) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The CSI is a 13-question tool that is used to measure strain related to care provision and to identify families with potential caregiving concerns. There is at least one item for each of the following major domains: Employment, Financial, Physical, Social, and Time. A 0 (No) to 1 (Yes) scale is used for each of the 13 questions; thus the total score ranges from 0 to 13. Higher scores signify higher stress levels. Positive responses to 7 or more items on the index indicate a greater level of strain. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Cornell Scale for Depression in Dementia (CSDD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The CSDD is a 19-item interview specifically developed to assess the signs and symptoms of major depression in participants with dementia. Each of the 19 items is rated for severity on a scale of 0 to 2 (0, absent; 1, mild or intermittent; 2, severe). The total score is calculated as the sum of the item scores and thus ranges from 0 to 38. Higher scores signify more severe depression. Scores above 10 indicate probable major depression. Scores above 18 indicate definite major depression. Scores below 6, as a rule, are associated with the absence of significant depressive symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Mini-Mental State Examination (MMSE) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline), as Analyzed by the Specified SPCD Methodology | The MMSE is a brief test that is used to screen for cognitive impairment. The MMSE scale comprises 11 questions or simple tasks concerning orientation, memory, attention, and language to evaluate the participant's cognitive state. The anchor values are not consistent for each task. The MMSE total score is calculated by summing the item scores across all 11 tasks. A participant's total possible MMSE score ranges from 0 to 30 points. Higher scores indicate milder cognitive impairment. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Quality of Life-Alzheimer's Disease (QoL-AD) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The QoL-AD is a brief, 13-item measure designed specifically to obtain a rating of the participant's quality of life (QoL) from both the participant and the caregiver. It uses simple and straightforward language and responses and includes assessments of the individual's relationships with friends and family, concerns about finances, physical condition, mood, and an overall assessment of life quality. Caregivers complete the measure as a questionnaire about the participants' QoL, whereas participants complete it in interview format about their own QoL. Each of the 13 items is rated on a 4-point scale, with 1 indicating a poor QoL and 4 indicating an excellent QoL. Total scores range from 13 to 52, with a higher score indicating a better QoL. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) Score From Day 1 (Stage 1 Baseline) to Day 36 (Stage 2 Baseline) and From Day 36 to Day 70 | The ADCS-ADL inventory measures basic activities of daily living such as dressing, conversation, eating, bathing, and grooming. The 19-item version, covering mainly basic ADL, is used to assess participants with more severe disabilities. The ADCS-ADL uses a scale from 0 to 54. Lower scores indicate declining ability. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Change in the NPI Agitation/Aggression Domain Score From Day 1 (Stage 1 Baseline) to Day 8 and Day 22 and From Day 36 (Stage 2 Baseline) to Day 43 and Day 57 | 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 was designed to collect information on the behavioral aspects of agitation/aggression in participants with probable 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, marked. The total domain score is calculated as the frequency score multiplied by the severity score and thus ranges from 1 to 12. A higher score represents worsening symptoms. Change from Baseline is calculated as the post-Baseline score minus the Baseline score. | Day 1 (Stage 1 Baseline); Days 8 and 22; Day 36 (Stage 2 Baseline); Days 43 and 57 | 
| Number of Participants With the Indicated Response on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Rating (mADCS-CGIC) Scale Agitation Domain at Day 36 and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) | 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 participant is 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 is defined as the last non-missing assessment prior to Stage 1 randomization. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Number of Participants With the Indicated Response on the mADCS-CGIC Scale Agitation Domain at Day 70 Compared to Their Response at Day 36 (Stage 2 Baseline) | 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 participant is 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. For placebo non-responders re-randomized to AVP-923 or placebo at Stage 2, Baseline is defined as the last non-missing assessment prior to Stage 2 re-randomization. | Day 36 (Stage 2 Baseline); Day 70 | 
| Number of Participants With the Indicated Categorical Response on the Patient Global Impression of Change (PGI-C) for the Caregiver Domain at Day 36 (Stage 2 Baseline) and Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) | The PGI-C uses a 7-point scale to assess treatment response and to rate the global impression of clinical change in a participant's agitation. The participant is asked to rate their impression of change from Baseline as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse. Baseline is defined as the last non-missing assessment prior to Stage 1 randomization. | Day 1 (Stage 1 Baseline); Day 36 (Stage 2 Baseline); Day 70 | 
| Number of Participants With the Indicated Categorical Response on the PGI-C for the Caregiver Domain at Day 70 Compared to Their Response at Day 1 (Stage 1 Baseline) | The PGI-C uses a 7-point scale to assess treatment response and to rate the global impression of clinical change in a participant's agitation. The participant is asked to rate their impression of change from Baseline as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse. For placebo non-responders re-randomized to AVP-923 or placebo at Stage 2, Baseline is defined as the last non-missing assessment prior to Stage 2 re-randomization. | Day 1 (Stage 1 Baseline); Day 70 | 
| Number of Participants With the Indicated Change in the Concomitant Use of Allowed Psychotropic Drugs Compared to Their Baseline Use | Concomitant medications (CMs) are defined as non-study medications with a start date on or before the final study visit, and that were either ongoing at the end of the study or had a stop date on or after the date of first dose of study drug. Drugs for the treatment of AD (e.g., donepezil, rivastigmine, galantamine, memantine) were allowed when administered at stable dose for at least 2 months prior to randomization. Concomitant use of the following medications was allowed, provided the participant had been on a stable dose for at least 1 month prior to randomization and remained stable throughout the study: medications for agitation secondary to AD; medications for nighttime management of insomnia or behavioral disturbances that included short-acting benzodiazepines, a low dose of alprazolam up to 0.5 milligrams (mg)/day, and a low dose of trazodone up to 50 mg/day; hypnotics for the treatment of insomnia; and certain classes of antidepressants. | up to Week 10 | 
| Number of Participants Using Rescue Medications | Participants were allowed to receive oral lorazepam as rescue medication for the short-term treatment of symptoms of agitation, if deemed necessary by the investigator. Lorazepam was to be administered at doses up to 1.5 mg/day, and dosing was not to exceed 3 days in any 7-day period. | up to Week 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AVP-923-20, AVP-923-30, AVP-923, Dextromethorphan, Quinidine, Neuropsychiatric Inventory, Aggression, Efficacy, Safety