Clinical Trials Register

Summary
EudraCT Number:	2020-000799-39
Sponsor's Protocol Code Number:	20-AVP-786-307
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-12-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2020-000799-39

A.3

Full title of the trial

A Phase 3, multicenter, randomized, double-blind, placebo-controlled 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.

Multicentrické, randomizované, dvojito zaslepené, placebom kontrolované klinické skúšanie fázy III na vyhodnotenie účinnosti, bezpečnosti a znášanlivosti AVP-786 (deudextrometorfániumhydrobromid [d6-DM]/chinidíniumsulfát [Q]) na liečbu agitácie u pacientov s demenciou Alzheimerovho typu

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to assess the efficacy, safety, and tolerability of AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer’s type.

Skúšanie na vyhodnotenie účinnosti, bezpečnosti a znášanlivosti produktu AVP-786 na liečbu agitácie u pacientov s demenciou Alzheimerovho typu

A.4.1

Sponsor's protocol code number

20-AVP-786-307

A.5.4

Other Identifiers

Name:

IND

Number:

124099

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Otsuka America Pharmaceutical, Inc.
B.5.2	Functional name of contact point	Anthony Agidotan
B.5.3	Address:
B.5.3.1	Street Address	2440 Research Blvd
B.5.3.2	Town/ city	Rockville
B.5.3.3	Post code	MD 20850
B.5.3.4	Country	United States
B.5.4	Telephone number	+49174940 -1793
B.5.6	E-mail	aagidotan@otsuka-europe.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]
D.3.2	Product code	AVP-786
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Deudextromethorphan Hydrobromide
D.3.9.1	CAS number	1373497-18-7
D.3.9.2	Current sponsor code	d6-DM
D.3.9.4	EV Substance Code	SUB191184
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	42.63
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Quinidine sulfate
D.3.9.1	CAS number	6591-63-5
D.3.9.2	Current sponsor code	Q
D.3.9.3	Other descriptive name	QUINIDINE SULFATE DIHYDRATE
D.3.9.4	EV Substance Code	SUB15083MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.9
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

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

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

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 (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.

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

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

different dosage of IMP - refer to blinded protocol page 10 for number of arms E.8.2.4 and dosage

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Chile

Colombia

Canada

Mexico

United States

Belgium

Croatia

Hungary

Ireland

Netherlands

Slovakia

Slovenia

Spain

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

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Eligible patients must have a reliable caregiver

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

260

F.4.2.2

In the whole clinical trial

750

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-10

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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