Assessment of the Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

Prior treatment

• 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 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 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 who have ever received DM co-administered with Q or d6-DM co-administered with Q.

Other illness

• 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 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.
• 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 with known hypersensitivity to DM, Q, opiate drugs (codeine, etc), or any other ingredient of the study drug.

Lab values

• 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.

Other

• Caregiver is unwilling or unable, in the opinion of the Investigator, to comply with study instructions.
• 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.
• Patients with myasthenia gravis (contraindication for quinidine).

• Males and females 50 to 90 years of age (inclusive) at the time of informed consent.
• 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.)
• 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)