Clinical Trials Register

Summary
EudraCT Number:	2016-004128-42
Sponsor's Protocol Code Number:	E2609-G000-302
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-06-02
Trial results	View 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

2016-004128-42

A.3

Full title of the trial

A Placebo-Controlled, Double-Blind, Parallel-Group, 24-Month Study to Evaluate the Efficacy and Safety of E2609 in Subjects with Early Alzheimer’s Disease

Placebo-kontrollos, kettős-vak, párhuzamos csoportos, 24 hónapos vizsgálat az E2609 hatásosságának és biztonságosságának értékelésére korai Alzheimer-kórban szenvedő betegek körében

A.3.1

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

A Placebo-Controlled, Double-Blind, Parallel-Group, 24-Month Study to Evaluate the Efficacy and Safety of E2609 in Subjects with Early Alzheimer’s Disease

A.4.1

Sponsor's protocol code number

E2609-G000-302

A.5.4

Other Identifiers

Name:

IND Number

Number:

109308

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	Eisai Ltd.
B.1.3.4	Country	United Kingdom
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	Eisai Ltd
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Eisai 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	Eisai Ltd.
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	Mosquito Way
B.5.3.2	Town/ city	Hatfield, Hertfordshire
B.5.3.3	Post code	AL10 9SN
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0044845676 1400
B.5.5	Fax number	0044845676 1486
B.5.6	E-mail	LMedInfo@eisai.net

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	Elenbecestat
D.3.2	Product code	E2609
D.3.4	Pharmaceutical form	Tablet
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	Elenbecestat
D.3.9.2	Current sponsor code	E2609
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	50
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	Tablet
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

Early Alzheimer Disease including mild cognitive impairment (MCI) due to AD/Prodromal AD and the early stages of mild AD

E.1.1.1

Medical condition in easily understood language

Clinical Dementia

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	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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10074616
E.1.2	Term	Prodromal 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

To determine whether elenbecestat (E2609) is superior to placebo on the change from baseline in the Clinical Dementia Rating - Sum Of Boxes (CDR-SB) at 24 months in subjects with Early Alzheimer’s Disease (EAD)

E.2.2

Secondary objectives of the trial

Secondary Objectives
•To evaluate the safety and tolerability of elenbecestat (E2609) in subjects with EAD
•To determine whether elenbecestat (E2609) is superior to placebo on the time to worsening of Clinical Dementia Rating (CDR) scores in subjects with EAD
•To determine whether elenbecestat (E2609) is superior to placebo on the time to conversion to dementia for subjects who were not clinically staged as having dementia at Baseline based on a clinical diagnosis evaluated every 3 months
•To determine whether elenbecestat (E2609) is superior to placebo on the rate of change over time (mean slope) based on CDR-SB score over 24 months in subjects with EAD
•To determine whether elenbecestat (E2609) is superior to placebo on the Alzheimer’s Disease Assessment Scale-Cognition14 (ADAS-cog14), Mini Mental State Examination (MMSE), and Functional Assessment Questionnaire (FAQ) at 24 months in subjects with EAD

Please refers to the Study Protocol for further objectives

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Two longitudinal biomarker substudies will evaluate the effects of study treatment on the underlying pathophysiology of AD using Amyloid PET and/or CSF biomarkers. Participation in the substudies is optional and will require specific consent that will not affect enrollment or treatment in the main study.

E.3

Principal inclusion criteria

1. MCI due to Alzheimer’s disease or Mild Alzheimer’s disease according to the National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria and must have all of the following:
a. MMSE score equal to or greater than 24
b. CDR global score of 0.5
c. CDR Memory Box score of 0.5 or greater
2. A history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; this MUST be corroborated by a study partner
3. Cognitive impairment of at least 1 SD from age-adjusted norms in total recall or delayed recall on the ISLT.
4. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following:
a. PET assessment of amyloid imaging agent uptake into brain. Note: Amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility.
b. CSF assessment of Aβ(1-42) NOTE: Subjects may undergo both the Amyloid PET and CSF assessments, but need a positive amyloid result in only 1 of the 2 procedures to confirm eligibility. Subjects who consent to Amyloid PET or CSF for eligibility purposes are not required to participate in the Amyloid PET or CSF longitudinal substudies. Use of a historical Amyloid PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility but will not suffice for the baseline assessment if the subject wishes to consent to the Amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor.
5. Male or female subjects between 50 and 85 years of age, inclusive at the time of consent
6. If receiving an AChEI or memantine or both for AD, must be on a stable dose for at least 12 weeks prior to Randomization. Treatment-naïve subjects with AD can be entered into the study.
7. Subjects must have been on stable doses of all other (ie, non-AD related) permitted concomitant medications for at least 4 weeks prior to Randomization, except for medications which are administered as short courses (eg, up to 3 weeks unless discussed and agreed with Medical Monitor) of treatment (eg, anti-infectives) or which are to be used on a Pro re nata (PRN) basis. Subjects who require a short course of treatment, such as an anti-infective, may be randomized once the acute illness has completely resolved, even if the concomitant medication continues.
8. Must have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must provide written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that they can reliably fulfill the requirements of being a study partner. A study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. Study partners need to provide input to the following assessments: CDR, FAQ, EQ-5D, QOL-AD, Zarit’s Burden Interview, and the clinical assessment of suicidality. Consideration can occur for the investigator to decide whether the study partner can provide information over the telephone or whether the study partner must attend the study visits in person with the subject.

E.4

Principal exclusion criteria

1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive
beta-human chorionic gonadotropin test. A separate baseline assessment is required if a negative
screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
Females of child-bearing potential who:
•Within 28 days before study entry, did not use a highly effective method of contraception,
which includes any of the following:
o total abstinence (if it is their preferred and usual lifestyle)
o an intrauterine device or intrauterine hormone-releasing system
o an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.)
o have a vasectomized partner with confirmed azoospermia.
•Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation.
For sites outside of the European Union, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a
medically acceptable method of contraception, ie, double-barrier methods of contraception such
as condom plus diaphragm or cervical/vault cap with spermicide.
NOTE: All females will be considered to be of child-bearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
2. Any condition that may be contributing to cognitive impairment above and beyond that caused by
the subject’s AD
3. Subjects with a history of seizures within 5 years of Screening or subjects with disturbance likely
to be due to seizures within 5 years of Screening
4. History of transient ischemic attacks (TIA) or stroke within 12 months of Screening
5. Modified Hachinski Ischemia Score greater than 4 at Screening
6. Any of the following psychiatric symptoms:
• Psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures
• Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, at Screening, or at the Randomization Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening
7. Have any contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (eg, in skull and cardiac devices other than those approved as safe
for use in MRI scanners) or
• Have any evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening.
• Exhibit other significant pathological findings on brain MRI at Screening, including but not limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be exclusionary).
8. Subjects who have a history of moderate to severe hepatic impairment (eg, Child-Pugh Class B or C). Any 2 of the following criteria at Screening would exclude the subject: INR ≥ 1.7; bilirubin ≥ 1.5 × ULN; albumin < LLN; ascites or hepatic encephalopathy. Please note that a single significant abnormality could meet criteria for moderate impairment. (revised per Amendment 01)
9. Results of laboratory tests conducted during screening that are outside the following limits:
• Absolute lymphocyte count (ALC) below Lower Limit of Normal (LLN) or below 800 per mm3 (whichever is higher); ALC will be derived from the complete blood count (CBC) with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they are present) and calculated by the white blood cell count × percentage of lymphocytes. (revised per Amendment 01)
• Thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator (this applies to all subjects whether or not they are taking thyroid supplements)
................ Please refers to study protocol for further exclusion criteria

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in the CDR-SB at 24 months

E.5.1.1

Timepoint(s) of evaluation of this end point

at 24 months

E.5.2

Secondary end point(s)

•Time to worsening of CDR scores by 24 months (eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is undertaken)
•Time to conversion to dementia by 24 months for subjects who were not clinically staged as dementia at Baseline based on clinical diagnosis
•The rate of change over time (mean slope) based on CDR-SB score over 24 months
•Change from baseline in CDR-SB at 27 months (ie, 24 months of treatment plus 3 months posttreatment follow-up)
•Change from baseline in ADAS-cog14, MMSE, and FAQ at 24 months
•Change from baseline in ADAS-cog14 Word List (immediate recall and delayed recall) at 24 months

Biomarker Endpoints
•Change from baseline in amyloid PET SUVR composite at 24 months for brain amyloid levels
•Change from baseline in CSF biomarkers t-tau and p-tau at 24 months
•Change from baseline in CSF amyloid biomarkers Aβ(1-40), Aβ(1-42), and Aβ(1-x) at 24 months
•Change from baseline in total hippocampal volume at 24 months using vMRI
•Change from baseline in the preservation of connectivity on fMRI at 24 months

Exploratory Endpoints
•Time to change of concomitant AD treatment (ie, dose increase and/or initiation of treatment with AChEI or memantine after randomization) by 24 months
•The proportion of subjects at 24 months who received dose increases and/or initiation of treatment with AChEI or memantine after randomization
•The rate of change over time (mean slope) based on NPI-10 item score over 24 months
•Change from baseline in NPI-10 item at 24 months
•Change from baseline in EQ-5D (subject self-reported, study partner self-reported, and subject measured by proxy) and QOL-AD (subject and study partner) at 24 months
•Change from baseline in Zarit’s Burden Interview at 24 months

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the relevant endpoint for the specific timepoint

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

quality of life

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

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

130

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

Canada

China

Czech Republic

Denmark

Finland

France

Germany

Hong Kong

Hungary

Italy

Japan

Korea, Republic of

Poland

Portugal

Singapore

Slovakia

South Africa

Spain

Taiwan

United States

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1130

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

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

400

F.4.2.2

In the whole clinical trial

1330

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)

All subjects, regardless of whether they complete all 24 months of treatment or discontinue study drug prematurely, will complete 2 post-treatment Follow-Up Visits (Visit 14 and Visit 15 respectively).

An open-label Extension Phase will be available for subjects who complete the full 24 months of treatment in the Core study. The Extension Phase will continue until commercial availability of E2609, or until a positive risk-benefit assessment in this indication is not demonstrated.

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

2017-08-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-01-14

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