Clinical Trials Register

Summary
EudraCT Number:	2016-004948-11
Sponsor's Protocol Code Number:	E2020-A001-335
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-03-09
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2016-004948-11

A.3

Full title of the trial

A 10-Week, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of Donepezil Hydrochloride (Aricept) In The Treatment Of The Cognitive Dysfunction Exhibited By Children With Down Syndrome, Aged 11 To 17

A.3.1

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

Evaluating The Efficacy And Safety Of Donepezil Hydrochloride (Aricept) In The Treatment Of The Cognitive Dysfunction Exhibited By Children With Down Syndrome, Aged 11 To 17

A.3.2

Name or abbreviated title of the trial where available

Not applicable

A.4.1

Sponsor's protocol code number

E2020-A001-335

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00754052

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 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	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 Inc.
B.5.2	Functional name of contact point	Eisai Medical Information
B.5.3	Address:
B.5.3.1	Street Address	100 Tice Boulevard
B.5.3.2	Town/ city	Woodcliff Lake, NJ
B.5.3.3	Post code	07677
B.5.3.4	Country	United States
B.5.4	Telephone number	011888274-2378

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	Yes
D.2.1.1.1	Trade name	Aricept
D.2.1.1.2	Name of the Marketing Authorisation holder	Eisai Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	donepezil hydrochloride
D.3.2	Product code	E2020
D.3.4	Pharmaceutical form	Oral liquid
D.3.4.1	Specific paediatric formulation	Yes
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	donepezil hydrochloride
D.3.9.1	CAS number	142057-77-0
D.3.9.2	Current sponsor code	E2020
D.3.9.3	Other descriptive name	DONEPEZIL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB13647MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Oral liquid
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

Down Syndrome, Cognitive Dysfunction

E.1.1.1

Medical condition in easily understood language

Down Syndrome

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

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 purpose of this study is to determine the efficacy and safety of donepezil hydrochloride (Aricept) in the treatment of the cognitive dysfunction shown by children with Down syndrome, aged 11 to 17.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age range: Participants 11 to 17 years of age at the screening visit; weight >35 kg.
2. Sex distribution: both males and females.
3. Vineland-II Adaptive Behavior Scale Patient/Caregiver Rating Form (VABS-II/PCRF) receptive sub-domain raw score of >= 25 and expressive sub-domain raw score of >= 61.
4. Clinical diagnosis of Down syndrome (DS) - participants may have free trisomy 21, Robertsonian translocations, or mosaic DS.
5. Naive to approved or unapproved cholinesterase inhibitors (Aricept, Exelon, Cognex, Reminyl/Razadyne, metrifonate, physostigmine) is preferred. However, prior use of these medications is allowed, provided that the medication was discontinued at least 3 months prior to screening and that it was not discontinued for lack of tolerability or efficacy or for the sole purpose of enrolling the participant in the study. The exception to this prior use is that participants who participated in the Phase II study E2020-A001-219 (A2501059) are not eligible.
6. Participants residing in the community or in facilities that have consistent and reliable caregivers who can provide efficacy information about the participants.
7. The participants must be expected to complete all procedures scheduled during the Screening and Baseline visits including all efficacy and safety parameters. Participants who are verbal and able to be understood most of the time are preferred, but those who use other forms of communication, signs, symbol boards or devices to supplement his/her communication ability may be enrolled provided they meet the VABS-II/PCRF receptive and expressive score criteria mentioned above.
8. Participants must have a parent, or other reliable caregiver who agrees to accompany the participant to all clinic visits, provide information about the participant as required by the protocol, and ensure compliance with the medication schedule.
9. The parent or caregiver must be a constant and reliable informant with sufficient contact with the participant to have detailed knowledge of the participant's adaptive functioning in order to be able to complete the VABS-II/PCRF accurately. The same individual should complete the form at every visit, if possible.
10. Participants should be in good general health with no medical conditions that are considered both clinically significant and unstable.
11. Clinical laboratory values within normal limits or abnormalities considered not clinically significant by the investigator and sponsor.
12. Participants with stable Type I (insulin-dependent) or Type II diabetes are eligible provided they are monitored regularly prior to and during the study to ensure adequate glucose control. (Adequacy of control is based on the investigator's judgment, but should be guided primarily by a glycosylated hemoglobin [hemoglobin A1c] <8.0 at screening; other information, including records of home monitoring and the screening fasting glucose may support this judgment).
13. Participants with thyroid disease also may be included in the study provided they are euthyroid and stable on treatment for at least 1 month prior to screening.
14. Participants with a history of seizure disorder are allowed provided that they are on stable treatment for at least 3 months and have not had a seizure within the past 6 months.
15. Participants should be independent in ambulation or ambulatory aided (i.e., walker or cane, to wheelchair); vision and hearing (eyeglasses and/or hearing aid permissible) sufficient for achieving VABS-II/PCRF minimum receptive raw scores of >= 25 and expressive scores of >= 61 and for cooperating with secondary efficacy evaluations and study examinations.
16. Females who have begun menstruation and are thus of child-bearing potential may be enrolled but must be documented not to be pregnant by serum pregnancy testing at screening. They also must be practicing an effective means of birth control (abstinence, oral contraceptives, hormonal implants in place at least 1 month prior to enrollment, or a double-barrier method), which must be documented, and the participant and caregiver must be counseled in writing of the importance of not becoming pregnant during the trial. A urine pregnancy test will be done at the Week 4 clinic visit and must be negative prior to dispensing any medication; a serum pregnancy test will be repeated at the Week 10 (or Early Termination) clinic visit.

E.4

Principal exclusion criteria

1. Age range: Participants <11 or >17 years at the screening visit.
2.Participants with active or clinically significant conditions that will, in the investigator's judgment, affect absorption, distribution or metabolism of the study medication (e.g., inflammatory bowel disease, gastric or duodenal ulcers or severe lactose intolerance); controlled celiac disease is allowed.
3. Participants with a known hypersensitivity to piperidine derivatives or cholinesterase inhibitors.
4. Participants currently receiving cholinesterase inhibitors or who have received them in the 3 months prior to screening or with prior use >3 months prior to screening who stopped for lack of efficacy or tolerability or simply to enroll the participant in this study. Also excluded are participants who participated in the Phase II study E2020-A001-219 (A2501059). In addition, participants may not have taken any other investigational medications (including memantine) within 3 months prior to screening.
5. Participants without a reliable parent or caregiver (caregiver responsibilities are described in the Inclusion Criteria above), or with parents or caregivers who are unwilling or unable to complete any of the outcome measures and fulfill the requirements of this study.
6. Participants with clinically significant obstructive pulmonary disease or asthma, untreated or not controlled by treatment within 3 months prior to screening.
7. Participants with recent (<= 1 year) or ongoing hematologic/oncologic disorders (mild anemia allowed).
8. Evidence of active, clinically significant, and unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease.
9. Participants with a current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of Major Depressive Disorder (MDD) or any current primary psychiatric diagnosis other than DS (as per DSM-IV). Diagnoses that are secondary, such as attention deficit hyperactivity disorder, are allowed.
10. Any condition which would make the participant or the caregiver, in the opinion of the investigator, unsuitable for the study. Unsuitability includes female participants who have begun menstruation and are thus of child-bearing potential, and who are not practicing an effective means of birth control. Female participants who have begun menstruation and are sexually abstinent or who are practicing another effective means of birth control are not excluded but must be counseled in writing along with their caregiver about the importance of not becoming pregnant during the study and must have a negative pregnancy test at screening and pregnancy testing at Weeks 4 and 10.

E.5 End points

E.5.1

Primary end point(s)

Mean change from baseline in VABS-II/PCRF score using last observation carried forward.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline (Day 0) to Visit 3 (Week 10) or early termination

E.5.2

Secondary end point(s)

Mean change from baseline in additional analyses of the VABS-II/PCRF
Mean change from baseline in Test of Verbal Expression and Reasoning (TOVER)
Mean change from baseline in the Forward Memory and Attention Sustained sub-tests of the Leiter-R.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline (Day 0) to Visit 3 (Week 10) or early termination

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

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

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

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

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

As per the protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

210

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

210

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

210

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Children <18 years old with Down Syndrome. Parent/legal representative provides consent on their behalf.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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