A Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-design study to assess the efficacy, safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide [d6-DM]/ quinidine sulfate [Q]) for the treatment of agitation in patients with dementia of the Alzheimer’s type.

Study ID: 37238
Short Title: Phase 3 of AVP-786 in Alzheimer’s dementia patients with agitation
Organisation: Southern Health NHS Foundation Trust
Location: Marc
Condition: Dementia
Main Specialty: Dementias
Expected End Date: 26/02/2021
Postcode: SO40 2RZ
Contact Name: R&D department
Contact Email: research@southernhealth.nhs.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

1. Males and females 50 to 90 years of age inclusive, at the time of informed consent. 2. Diagnosis of probable AD according to the 2011 NIA-AA working groups criteria. Either outpatients or residents of an assisted-living facility or a skilled nursing home. 3. The patient has clinically significant, moderate/severe agitation at the time of screening and for at least 2 weeks prior to randomisation, that interferes with daily routine and for which a prescription medication is indicated, in the opinion of the investigator. 4. The diagnosis of agitation must meet the IPA provisional definition of agitation. 5. CGIS-Agitation score is > = 4 (moderately ill) at Screening and Baseline. 6. MMSE score between 6 and 26 (inclusive) at Screening and Baseline. 7. The patient has stable cardiac, pulmonary, hepatic, and renal function. 8. The patient has an ECG (obtained within the past month prior to randomisation and evaluated by a central ECG reader) with no clinically significant findings. 9. If female of childbearing potential, must have been practicing a medically-acceptable method of birth control for at least 1 month prior to randomisation and continue with the same method during the entire study duration (oral contraceptive tablets, hormonal implant device, hormone patch, intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, or abstinence) or be surgically sterile or post-menopausal. 10. Use of medication for the treatment of AD (e.g., donepezil, rivastigmine, galantamine, memantine) is allowed provided the dose has been stable for at least 3 months prior to randomisation. 11. Concomitant use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, citalopram), serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, desvenlafaxine, duloxetine) are allowed, provided the dose has been stable for at least 1 month prior to randomization and is within the Package Insert guidance for that medication. Paroxetine, a CYP2D6 substrate, is allowed provided the dose does not exceed 10 mg/day. 12. Concomitant use of hypnotics at bedtime (e.g., eszopiclone, zolpidem, zaleplon, trazodone [up to 50 mg/day]) for the night time treatment of insomnia is allowed, provided the dose has been stable for at least 1 month prior to randomization and remains stable throughout the study. In addition, concomitant use of short acting benzodiazepines (e.g., midazolam, oxazepam, low dose alprazolam [up to 0.5mg/day]) for behavioural disturbances is allowed. 13. Patients currently taking allowed medications for the treatment of agitation secondary to AD (e.g., atypical antipsychotics, antidepressants, buspirone) are eligible provided they have been on a stable dose for at least 2 weeks prior to screening and at least 1 month prior to randomisation. 14. Patient must not show current and significant symptoms of a depressive disorder and must have a score < 10 in The Cornell Scale for Depression in Dementia (CSDD) at Screening. 15. Patient must have no history or current clinical symptoms of schizophrenia, schizoaffective disorder, or bipolar disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). 16. Caregiver must be willing and able to comply with study procedures, including not administering any prohibited medications during the course of the study. 17. 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 authorised representative agrees to participation (for patients unable to provide assent) are allowed.

1. Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study instructions. 2. Patient has dementia predominantly of non-Alzheimer’s type (e.g., vascular dementia, frontotemporal dementia, Parkinson’s disease, substance-induced dementia). 3. Patients with symptoms of agitation that are not secondary to AD (e.g., secondary to pain, other psychiatric disorder, or delirium). 4. Patients with myasthenia gravis (contraindication for quinidine). 5. Patients with any personal history of complete heart block, QTc prolongation, or torsades de pointes. a. Screening and Baseline QTcF of > 450 msec for males and > 470 msec for females based on central review unless due to ventricular pacing b. Presence of premature ventricular contractions (PVCs) as evaluated by a central reader and deemed clinically significant by the investigator 6. Patients with any family history of congenital QT interval prolongation syndrome. 7. Patients with known hypersensitivity to DM, Q, opiate drugs (codeine, etc.), or any other ingredient of the study medication. 8. Patients with history of allergy to benzodiazepines (e.g., lorazepam). 9. Patients who have ever received DM co-administered with Q. 10. Patients who have been taking disallowed concomitant medications within 2 weeks or 5 half-lives, whichever is longer, prior to Baseline. 11. Patients 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 or untreated prostate cancer], 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 non-metastatic cancer may be allowed. Each case to be evaluated individually with the Medical Monitor (MM). 12. Patients who are currently participating in, or who have participated in other interventional (drug or device) clinical study within 30 days of Baseline. 13. Patients with history of postural syncope, or any history of unexplained syncope (evaluated on a case by case basis) within 12 months of Baseline. 14. Patients with a history of substance and/or alcohol abuse within the past 1 year. 15. Patients determined to have a high imminent risk of falls during the study based on a clinical evaluation by the investigator. 16. Patients with evidence of serious risk of suicide at Screening and Baseline based on the Sheehan Suicidality Tracking Scale (S-STS), i.e., 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.

This study will be conducted to evaluate the efficacy, safety, and tolerability of AVP-786 compared to placebo, for the treatment of agitation in participants with dementia of the Alzheimer's type. Eligible participants for this study must have a diagnosis of probable Alzheimer's disease (AD) and must have clinically significant, moderate/severe agitation secondary to AD. This is a multicenter, randomized, double-blind, placebo-controlled, parallel-design study, consisting of 12 weeks of treatment. Approximately 550 participants will be enrolled at approximately 90 centers worldwide. Study medication will be administered orally twice-daily from Day 1 through Day 85. Screening will occur 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.

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