Phase 3 Randomized, Double‑Blind, Placebo‑Controlled Study of AVP‑786 (deudextromethorphan hydrobromide/quinidine) for Agitation in Alzheimer’s Dementia

Trial ID: 2023-504990-19-00
Protocol: 20-AVP-786-306
Sponsor: Otsuka Pharmaceutical Development & Commercialization Inc.

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this study is to evaluate the **efficacy**, safety, and tolerability of AVP-786 compared to placebo for the treatment of **agitation** in patients with dementia of the Alzheimer's type. This is clinically relevant as agitation is a common and distressing symptom in Alzheimer's disease, impacting both patients and caregivers, and effective management can significantly improve quality of life.

Secondary objectives include:

Evaluating the effects of AVP-786 compared to placebo on global assessments of severity and improvement of agitation.
Assessing the effects on **neuropsychiatric symptoms**.
Examining the impact on measures of quality of life and resource utilization.

These objectives aim to provide a comprehensive understanding of the potential benefits of AVP-786 beyond its primary therapeutic effects, addressing broader aspects of patient well-being and healthcare resource management.

Participants

The clinical trial involves a total of **483 participants** diagnosed with **agitation in patients with dementia of the Alzheimer's type**. The study population comprises both male and female subjects, aged between 50 and 90 years. Participants were selected based on specific inclusion criteria, including a diagnosis of probable Alzheimer's disease according to the 2011 NIA-AA working groups criteria, and a **Mini-Mental State Examination (MMSE)** score between 8 and 24. The trial includes individuals who are either outpatients or residents of long-term care facilities. Participants must have clinically significant, moderate-to-severe agitation that interferes with their daily routine and require pharmacotherapy for agitation management. The trial population is characterized by stable cardiac, pulmonary, hepatic, and renal function as per the investigator's judgment. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a caregiver willing to comply with study procedures. The trial includes a vulnerable population, reflecting the cognitive impairments associated with Alzheimer's disease.

Plans and Procedures

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of **AVP-786** for the treatment of agitation in patients with dementia of the Alzheimer's type. The trial involves the administration of AVP-786, which contains the active substances **quinidine sulfate** and **deudextromethorphan hydrobromide**, in capsule form, compared to a matching placebo. The study is expected to run from July 2020 to March 2026, with a maximum treatment period of 85 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical history, and current health status. This visit will include evaluations like the **Mini-Mental State Examination (MMSE)** and assessments of agitation severity. Eligible participants will then be randomized to receive either AVP-786 or placebo. Follow-up visits will occur regularly to monitor the participants' health, adherence to the study protocol, and any adverse events. The primary efficacy endpoint is the change from baseline to the end of the efficacy period in the **Cohen-Mansfield Agitation Inventory (CMAI)** total score, while a key secondary endpoint is the change in the **Clinical Global Impression-Severity (CGI-S)** score related to agitation.

The expected length of participant involvement is approximately 85 days, with conditions for early termination including significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The study aims to provide comprehensive data on the potential benefits and risks of AVP-786 in managing agitation in Alzheimer's patients, contributing valuable insights into treatment options for this challenging condition.

Treatment

The clinical trial involves the administration of **AVP-786**, an experimental medication formulated as a **capsule**. The active substances in AVP-786 are **quinidine sulfate** and **deudextromethorphan hydrobromide**. The medication is administered orally. The maximum daily dose is 85.26 mg, with a total maximum dose of 7247.1 mg over a treatment period of 85 days. The medication is developed by Otsuka Pharmaceutical Development & Commercialization, Inc. The trial aims to evaluate the efficacy, safety, and tolerability of AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer's type.

In addition to the experimental medication, the study includes a **placebo** group. The placebo is designed to match AVP-786 in appearance and is also administered in capsule form. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. This allows for an unbiased assessment of the experimental medication's effects compared to the placebo.

Efficacy

The efficacy of AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer's type will be assessed in a Phase 3, multicenter, randomized, double-blind, placebo-controlled study. The primary efficacy endpoint is the change from baseline to the end of the efficacy period in the **Cohen-Mansfield Agitation Inventory (CMAI)** total score. This endpoint will be measured to evaluate the reduction in agitation symptoms.

The key secondary efficacy variable is the change from baseline to the end of the efficacy period in the **Clinical Global Impression-Severity (CGI-S)** score, specifically related to agitation. This secondary endpoint will be analyzed using the same statistical methodology as the primary efficacy variable. The procedure to control the overall type I error rate for this key secondary efficacy analysis will be detailed in the Statistical Analysis Plan (SAP).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Males and females 50 to 90 years of age (inclusive) at the time of informed consent.
Diagnosis of probable Alzheimer’s disease according to the 2011 NIA-AA working groups criteria. Either outpatients or residents of an assisted living facility, a skilled nursing home, a dementia unit, or any other type of facility providing long-term care.
MMSE score between 8 and 24 (inclusive) at Screening and Baseline.
Patient has clinically significant, moderate-to-severe agitation for at least 2 weeks prior to Screening that interferes with daily routine per the Investigator’s judgment.
Patients who require pharmacotherapy for the treatment of agitation per the Investigator’s judgment, after: •An evaluation of reversible factors (eg, pain, infection, or polypharmacy), and •A course of nonpharmacological interventions (eg, redirecting behavior, group activities, music therapy).
Diagnosis of agitation must meet the International Psychogeriatric Association (IPA) provisional definition of agitation.
NPI-AA total score (frequency × severity) must be ≥ 4 at Screening and Baseline.
Patient must meet an additional predetermined blinded eligibility criterion.
Patient has stable cardiac, pulmonary, hepatic, and renal function per the Investigator’s judgment. (For Germany only, the following text is in addition to the preceding text: The eligibility of patients with non-exclusionary but abnormal/out of range laboratory results will be assessed on a case-by-case basis by the Investigator and Medical Monitor. The criteria below are the objective non-exclusionary limits defining stable cardiac hepatic, renal, hematologic, and pulmonary function at Screening and Baseline to provide guidance to the Investigator and Medical Monitor: a. Creatine kinase ≤3X upper limit of normal (ULN) (U/L) b. Alanine aminotransferase (ALT) ≤3X ULN U/L, aspartate aminotransferase (AST) ≤3X ULN U/L, gamma glutamyl transferase (GGT) ≤3X ULN U/L, and total bilirubin ≤2X ULN U/L c. Creatinine ≤1.8 mg/dL d. Platelets ≥100 G/I e. Chronic obstructive pulmonary disease (COPD) criteria: FEV1 ≥ 50% predicted)
No clinically significant findings on the Screening ECGs based on central review and on the Baseline predose ECG based on the machine read and Investigator’s evaluation (per Exclusion Criterion 6).
Women who are of childbearing potential and are sexually active must use an effective method of birth control for at least 1 month prior to the Baseline, during participation in the study, and for at least 30 days after the last dose of study drug. The following requirements must be met: • Women who are of childbearing potential must use 2 of the following precautions in order to minimize the risk of failure of 1 method of birth control: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth control depot injection, birth control implant, or condom with spermicide or sponge with spermicide. Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods), declaration of abstinence for the duration of exposure to study drug, or withdrawal are not acceptable methods of contraception. • Women who are sterile (ie, had an oophorectomy and/or hysterectomy), postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause), or practice true abstinence (when this method is in line with the preferred and usual lifestyle of the patient) are exempt from this requirement. • Women who are lactating, pregnant, or plan to become pregnant are not eligible for participation in the study. (For Germany, Denmark, and Portugal only, the following text replaces the above: • Patient must be postmenopausal [defined as 12 consecutive months with no menses without an alternative medical cause] or surgically sterile [ie, had an oophorectomy and/or hysterectomy]. • Patients who are of childbearing potential, lactating, pregnant, or plan to become pregnant are not eligible for participation in the study.)
For restricted and prohibited concomitant medications, patients willing and able to meet all protocol requirements for duration of stability or washout prior to study entry and during the study (see Table 3 Restricted and Prohibited Concomitant Medications and Appendix 1 Prohibited Concomitant Medications).
Caregiver must be willing and able to comply with all study procedures, including adherence to administering study drug and not administering any prohibited medications during the study. The caregiver must spend a minimum of 2 hours with the patient per day for at least 4 days per week to qualify as caregiver. (For Bulgaria only, the following text replaces the requirement for the caregiver to spend a minimum of 2 hours with the patient for at least 4 days per week: The caregiver must spend a minimum of 2 hours per day per week with the patient to qualify as a caregiver.)
Patient/caregiver must be willing to sign and receive a copy of patient/caregiver informed consent form (ICF) after the nature and risks of study participation have been fully explained. Patients who are not capable of signing the ICF but are able to provide assent, or the patient’s authorized representative agrees to participation (for patients unable to provide assent) are allowed. (For Germany only, the following text is in addition to the above: The patient’s cognitive function must be assessed for all patients by an independent medical specialist, not affiliated with the study, to determine the ability of the patient to sign an informed consent prior to enrollment. Patient/caregiver must be willing to sign and receive a copy of patient/caregiver informed consent form (ICF) after the nature and risks of study participation have been fully explained. For patients who are not capable of signing the ICF due to cognitive impairment, a legal or authorized representative must be identified to provide informed consent.)

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Exclusion Criteria

Caregiver is unwilling or unable, in the opinion of the Investigator, to comply with study instructions.
Patient has dementia predominantly of non-Alzheimer’s type (eg, vascular dementia, frontotemporal dementia, Parkinson’s disease, substance-induced dementia).
Patients with symptoms of agitation that are not secondary to Alzheimer’s dementia (eg, secondary to pain, other psychiatric disorder, or delirium).
Patients who have been diagnosed with an Axis 1 disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision [DSM-5] criteria) including, but not limited to: • Schizophrenia, schizoaffective disorder, or other psychotic disorders not related to dementia • Bipolar I or II disorder, bipolar disorder not otherwise specified • Current Major Depressive Episode: Patients with a history of major depressive disorder, that is currently not symptomatic, are eligible. Patients currently on a stable dose(s) of allowed antidepressant medication(s) for at least 3 months prior to the Screening visit are eligible.
Patients with myasthenia gravis (contraindication for quinidine).
Patients with any personal history of complete heart block, QTc prolongation, or torsades de pointes. a. Screening and Baseline predose QT interval corrected for heart rate using the Fridericia’s formula (QTcF) of > 450 msec for males and > 470 msec for females unless due to ventricular pacing (See Section 8.1.5). Screening ECGs will be based on central review. Baseline predose ECG will be based on the machine read and Investigator’s evaluation; if the QTcF result from the machine read is exclusionary, do not administer study drug and please contact a Medical Monitor. b. Presence of premature ventricular contractions (PVCs) as evaluated by a central reader and deemed clinically significant by the Investigator.
Patients with any family history of congenital QT interval prolongation syndrome.
Patients with known hypersensitivity to DM, Q, opiate drugs (codeine, etc), or any other ingredient of the study drug.
Patients who have ever received DM co-administered with Q or d6-DM co-administered with Q.
Patients who would be likely to require a prohibited concomitant medication during the study (see Table 3, Restricted and Prohibited Concomitant Medications and Appendix 1 Prohibited Concomitant Medications).
Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (eg, 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). Certain other nonmetastatic cancer may be allowed. Each case is to be evaluated individually with a Medical Monitor.
Patients who are currently participating in or who have participated in other interventional (drug or device) clinical study, or found to be a “Virtually Certain” match in Clinical Trial Subject Database (CTSdatabase) with a patient who has participated in another interventional drug or device study within 30 days of Baseline.
Patients with history of postural syncope or any history of unexplained syncope (evaluated on a case-by-case basis) within 12 months of Baseline.
Patients with a history of substance and/or alcohol abuse within 12 months of Baseline.
Patients determined to have a high imminent risk of falls during the study based on a clinical evaluation by the Investigator.
Patients with evidence of serious risk of suicide at Screening and Baseline based on the Sheehan Suicidality Tracking Scale (S-STS), ie, a score of 3 or 4 on any one question 2 through 6 or 11, or a score of 2 or higher on any one question 1a, 7 through 10, or 12, or who in the opinion of the Investigator present a serious risk of suicide.
Patients who, in the opinion of the Investigator, Medical Monitor, or Sponsor, should not participate in the study.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	13 Jul 2020	124
Denmark	Not Recruiting	13 Jul 2020	15
Estonia	Not Recruiting	13 Jul 2020	13
Germany	Not Recruiting	13 Jul 2020	30
Greece	Not Recruiting	13 Jul 2020	28
Poland	Not Recruiting	13 Jul 2020	27
Portugal	Not Recruiting	13 Jul 2020	30