Clinical Trials Register

Summary
EudraCT Number:	2017-002455-29
Sponsor's Protocol Code Number:	15-AVP-786-303
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-05-30
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2017-002455-29

A.3

Full title of the trial

A Phase 3, Multicenter, Long-term, Extension Study of the Safety and Efficacy of AVP-786
(deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the Treatment
of Agitation in Patients with Dementia of the Alzheimer’s Type

A.3.1

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

Extension Study of AVP-786 in the Treatment of Subjects with Agitation Associated with Dementia of the Alzheimer's Type

A.4.1

Sponsor's protocol code number

15-AVP-786-303

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02446132

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	Avanir Pharmaceuticals, 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	Avanir Pharmaceuticals 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	Avanir Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Agitation Project Team
B.5.3	Address:
B.5.3.1	Street Address	30 Enterprise, Suite 200
B.5.3.2	Town/ city	Aliso Viejo, California
B.5.3.3	Post code	92656
B.5.3.4	Country	United States
B.5.4	Telephone number	0019492685912
B.5.5	Fax number	0019492422486
B.5.6	E-mail	17.AVP.786.303@avanir.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	AVP-786 (d6-DM 18/Q 4.9) (d6-DM: deudextromethorphan hydrobromide, Q: quinidine sulphate)
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 MONOHYDRATE
D.3.9.1	CAS number	1373497-18-7
D.3.9.2	Current sponsor code	d6-DM
D.3.9.3	Other descriptive name	Deudextromethorphan Hydrobromide
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	18
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.IMP: 2
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	AVP-786 (d6-DM 28/Q 4.9) (d6-DM: deudextromethorphan hydrobromide, Q: quinidine sulphate)
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
D.3.9.1	CAS number	1373497-18-7
D.3.9.2	Current sponsor code	d6-DM
D.3.9.3	Other descriptive name	Deudextromethorphan Hydrobromide
D.3.9.4	EV Substance Code	SUB191183
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	28
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/g milligram(s)/gram
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.IMP: 3
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	AVP-786 (d6-DM 42.63/Q 4.9) (d6- DM: deudextromethorphan hydrobromide, Q: quinidine sulphate)
D.3.2	Product code	AVP-786
D.3.4	Pharmaceutical form
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
D.3.9.1	CAS number	1373497-18-7
D.3.9.2	Current sponsor code	d6-DM
D.3.9.3	Other descriptive name	Deudextromethorphan Hydrobromide
D.3.9.4	EV Substance Code	SUB191183
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Agitation Associated with Dementia of the Alzheimer's Type

E.1.1.1

Medical condition in easily understood language

Agitation behavior associated with Alzheimer's disease

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10001497
E.1.2	Term	Agitation
E.1.2	System Organ Class	10037175 - Psychiatric 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

Evaluation of the long-term safety and maintenance of efficacy of AVP-786 for the treatment of agitation in patients with dementia of the Alzheimer’s type.

E.2.2

Secondary objectives of the trial

None

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient has successfully completed Studies 15-AVP-786 301, 15-AVP-
786-302, 17-AVP-786-305, or 12-AVR-131 and is deemed eligible
forenrollment by the investigator after review of theinclusion/exclusion
criteria.
8. Patient has stable cardiac, pulmonary, hepatic, and renal function.
10. If female of childbearing potential, must have been practicing a
medically-acceptable method of birth control 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.
15. Patients from Study 12-AVR-131 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
for. Patients rolling over from Studies 15-AVP-786-301, 15-AVP-786-
302, and 17-AVP-786-305 with scores greater than 10 in the CSDD at
baseline should be evaluated by the investigator for enrollment in the
current study.
17. Caregiver must be willing and able to comply with study procedures,
including not administering any prohibited medications during the
course of the study.
18. 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. Patient is currently participating in, or has participated in other
interventional (drug or device)
clinical study since exiting Studies 15-AVP-786-301, 15-AVP-786-302,
and 17-AVP-786-305, or within 30 days prior to baseline for patients
from Study 12-AVR-131.
2. Caregiver is unwilling or unable, in the opinion of the investigator, to
comply with study instructions.
3. 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
nonmetastatic cancer
may be allowed. For patients from Study 12-AVR-131, each case to be
evaluated individually with the Medical Monitor (MM).
4. Patients determined to have a high imminent risk of falls during the
study based on a clinical evaluation by the investigator
6. Patients who are currently using or were on NUEDEXTA® in the 2
weeks preceding Baseline.
7. Patients with evidence of serious risk of suicide at Screening (patients
from Study 12-AVR-131) 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.

E.5 End points

E.5.1

Primary end point(s)

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), Sheehan Suicidality Tracking Scale (S-STS), Mini Mental State Examination (MMSE), and the Epworth Sleepiness Scale (ESS). Pregnancy tests will be conducted for females of childbearing potential.

E.5.1.1

Timepoint(s) of evaluation of this end point

AE (every visit), PE (Baseline and V8), VS (every visit minus f/u), CLA (Baseline, V2, V3, V4, V5, V6, V7, V8), ECG (Baseline, V2, V3, V4, V5, V6, V7, V8), S-STS (All visits), MMSE (Baseline, V5 and V8), ESS (Baseline, V5 and V8), Pregnancy (Baseline, V2, V3, V4, V5, V6, V7, V8).

E.5.2

Secondary end point(s)

EFFICACY: Efficacy will be assessed using the Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI) agitation/aggression, irritability/lability, and aberrant motor behavior domains, modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change-Agitation (mADCS-CGICAgitation), Clinical Global Impression of Severity of Illness scale-Agitation (CGIS-Agitation), Patient Global Impression of Change (PGIC-rated by caregiver), Dementia Quality of Life (DEMQOL), Resource Utilization in Dementia (RUD) and EuroQol 5-Dimension 5-Level (EQ-5D-5L).

E.5.2.1

Timepoint(s) of evaluation of this end point

CMAI (Baseline, V4, V5, V6, V8, F/U V1&2), NPI agitation/aggression (Baseline, V4, V5, V6, V8), NPI irritability/lability and aberrant motor behavior domains (Baseline, V5, V8), mADCS-CGICAgitation (Baseline, V5, V8, F/U V1&2), CGIS-Agitation (Baseline, V4, V5, V6, V8), PGIC-rated by caregiver (Baseline, V4, V5, V6, V8), DEMQOL (Baseline, V5, V8), RUD (Baseline, V5, V8) and EQ-5D-5L (Baseline, V5, V8).

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

E.8.1.1

Randomised

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

different dose of AVP-786 depending on the last treatment received in the preceding study

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

100

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

Australia

Canada

South Africa

United States

Belgium

Bulgaria

France

Hungary

Italy

Poland

Romania

Spain

United Kingdom

Czechia

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

LVLS

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:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

750

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

Yes

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

Patients with agitation secondary to dementia of the Alzheimer's type

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

250

F.4.2.2

In the whole clinical trial

1200

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)

After a patient has ended the study, usual treatment will be
administered.

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

2018-07-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-23

P. End of Trial
P.	End of Trial Status	Ongoing

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Orphan Designation Number:
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