Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan Hydrobromide/Quinidine Sulfate) in Treating Agitation in Alzheimer's Dementia Patients

Trial ID: 2023-504991-31-00
Protocol: 20-AVP-786-307
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 of AVP-786 compared to placebo on neuropsychiatric symptoms.
Investigating the effects of AVP-786 compared to placebo on measures of quality of life and resource utilization.

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

Participants

The clinical trial involves a total of **502 participants** diagnosed with **agitation in patients with dementia of the Alzheimer's type**. The study population includes 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 and a clinically significant level of agitation that interferes with daily routines. The trial population comprises individuals who are either outpatients or residents of long-term care facilities, such as assisted living facilities or skilled nursing homes. Participants are required to have stable cardiac, pulmonary, hepatic, and renal function, as well as no clinically significant findings on screening ECGs. Lifestyle considerations include the requirement for caregivers to spend a minimum of 2 hours with the patient per day for at least 4 days per week. The trial also includes a vulnerable population, as it involves individuals with cognitive impairments. The selection process ensures that participants meet the necessary health and lifestyle criteria to evaluate the efficacy, safety, and tolerability of the investigational drug AVP-786 compared to placebo.

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 September 11, 2020, to October 30, 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, diagnosis of probable Alzheimer's disease, and the presence of clinically significant agitation. Following successful screening, participants will be randomized to receive either AVP-786 or placebo. The trial includes regular follow-up visits to monitor the participants' health, adherence to the study protocol, and any adverse events. The primary endpoint is the change in the **Cohen-Mansfield Agitation Inventory (CMAI)** total score from baseline to the end of the efficacy period, 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, withdrawal of consent, or non-compliance with study procedures. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to ensure participant safety and collect data for analysis. The trial is conducted under strict adherence to ethical guidelines, ensuring that all participants provide informed consent and that their health and well-being are prioritized throughout the study.

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 the treatment period. The treatment duration is set for a maximum of 85 days. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental medication, the study includes the use of a **placebo** control, specifically the **AVP-786 matching placebo**. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the study remains double-blind. The placebo is also administered orally in capsule form, with the same frequency and duration as the experimental treatment. This allows for a direct comparison of the efficacy, safety, and tolerability of AVP-786 against the placebo in treating agitation in patients with dementia of the Alzheimer's type.

Efficacy

The efficacy of AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer's type will be assessed using specific endpoints. 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 score is a validated tool used to measure agitation levels in patients. Additionally, a 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, with procedures to control the overall type I error rate 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.
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.
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.
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 Slovakia 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). • Women 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.
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.
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.

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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 questions 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
Belgium	Not Recruiting	11 Sept 2020	17
Croatia	Not Recruiting	11 Sept 2020	35
Hungary	Not Recruiting	11 Sept 2020	39
Ireland	Not Recruiting	11 Sept 2020	11
The Netherlands	Not Recruiting	11 Sept 2020	—
Slovakia	Not Recruiting	11 Sept 2020	59
Slovenia	Not Recruiting	11 Sept 2020	35
Spain	Not Recruiting	11 Sept 2020	30
Netherlands	—	—	22