Agitation in patients with dementia of the Alzheimer’s type MedDRA version: 21.1 Level: LLT Classification code 10001499 Term: Agitation mental System Organ Class: 10037175 - Psychiatric disorders MedDRA version: 20.0 Level: PT Classification code 10012271 Term: Dementia Alzheimer's type System Organ Class: 10029205 - Nervous system disorders MedDRA version: 20.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Product Name: deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]
Product Code: AVP-786
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Deudextromethorphan Hydrobromide
CAS Number:
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Males and females 50 to 90 years of age (inclusive) at the time of informed consent. 2. 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. 3. MMSE score between 8 and 24 (inclusive) at Screening and Baseline. 4. 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. 5. 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). 6. Diagnosis of agitation must meet the International Psychogeriatric Association (IPA) provisional definition of agitation. 7. NPI-AA total score (frequency × severity) must be = 4 at Screening and Baseline. 8. Patient must meet an additional predetermined blinded eligibility criterion. 9. Patient has stable cardiac, pulmonary, hepatic, and renal function per the Investigator’s judgment. 10. 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. 11. 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.) 12. 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 protocol Table 3 Restricted and Prohibited Concomitant Medications and Appendix 1 Prohibited Concomitant Medications). 13. 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. 14. 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 188 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 562
Exclusion criteria
Exclusion criteria: 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 (eg, vascular dementia, frontotemporal dementia, Parkinson’s disease, substance-induced dementia). 3. Patients with symptoms of agitation that are not secondary to Alzheimer’s dementia (eg, secondary to pain, other psychiatric disorder, or delirium). 4. 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. 5. Patients with myasthenia gravis (contraindication for quinidine). 6. 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. 7. Patients with any family history of congenital QT interval prolongation syndrome. 8. Patients with known hypersensitivity to DM, Q, opiate drugs (codeine, etc), or any other ingredient of the study drug. 9. Patients who have ever received DM co-administered with Q or d6-DM co-administered with Q. 10. 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). 11. 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. 12. 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. 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 12 months of Baseline. 15. Patients determined to ha
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective 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.;Secondary Objective: ? Evaluate the effects of AVP-786 compared to placebo on global assessments of severity and improvement of agitation ? Evaluate the effects of AVP-786 compared to placebo on neuropsychiatric symptoms ? Evaluate the effects of AVP-786 compared to placebo on measures of quality of life and resource utilization;Primary end point(s): 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 ;Timepoint(s) of evaluation of this end point: from Baseline to the end of trial | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Efficacy Measure: Clinical Global Impression of Severity of Illness for Agitation (CGIS-Agitation) Other efficacy measures include: ? Change from baseline to each study visit in efficacy period in CMAI Total score ? Change from baseline to each study visit in efficacy period in CGIS-Agitation score ? CGIC-Agitation score at each study visit in the efficacy period ? Change from baseline to each study visit in efficacy period in NPI-AA score ? Change from baseline to each study visit in efficacy period in NPI total score ? CMAI Response Rate at each study visit in efficacy period, where response is defined as = 30% reduction in CMAI Total Score from baseline ? CMAI Response Rate at each study visit in efficacy period, where response is defined as = 50% reduction in CMAI Total Score from baseline ? Change from baseline to each study visit in efficacy period in the EQ-5D-5L total score ? Change from baseline to each study visit in efficacy period in the RUD-Lite Safety: Safety and tolerability of AVP-786 will be assessed by reported adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory assessments, resting 12-lead electrocardiograms (ECGs), MMSE, the Epworth Sleepiness Scale (ESS), and the Sheehan Suicidality Tracking Scale (S-STS).;Timepoint(s) of evaluation of this end point: from Baseline to the end of trial | — |
Countries
Belgium, Canada, Chile, Colombia, Croatia, Hungary, Ireland, Mexico, Netherlands, Slovakia, Slovenia, Spain, United States
Contacts
Public ContactAnthony Agidotan
Otsuka America Pharmaceutical, Inc.
Outcome results
None listed