| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Agitation in patients with dementia of the Alzheimer’s type |
|
| E.1.1.1 | Medical condition in easily understood language |
| Agitation due to Alzheimer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001499 |
| E.1.2 | Term | Agitation mental |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
| E.1.2 | Term | Dementia Alzheimer's type |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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, and•A course of nonpharmacological
interventions. 6.Diagnosis of agitation must meet the International
Psychogeriatric Association (IPA) provisional definition of
agitation.7.NPI-AA total score 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. (For Germany only: 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) 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. (per Exclusion Criterion 6). 11.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, declaration of abstinence for the duration of exposure to
study drug, or withdrawal are not acceptable methods of contraception.•
Women who are sterile, postmenopausal, or practice true abstinence 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: •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.) 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. 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. (For Bulgaria only:
The caregiver must spend a minimum of 2 hours per day per week with
the patient to qualify as a 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. (For
Germany only: 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.) |
|
| E.4 | Principal 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 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), 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.
17. Patients who, in the opinion of the Investigator, Medical Monitor, or sponsor, should not participate in the study. |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from Baseline to the end of trial |
|
| E.5.2 | 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| from Baseline to the end of trial |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| United Kingdom |
| United States |
| Bulgaria |
| Denmark |
| Estonia |
| Germany |
| Greece |
| Poland |
| Portugal |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as the “Last Patient Last Visit”, which is the date on which the last patient has his or her last visit (ie, the Follow-up visit) or assessment either for therapeutic or follow-up purposes. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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