Summary
EudraCT Number: 2018-003426-89
Sponsor's Protocol Code Number: E2020-J081-345
Clinical Trial Type: Outside EU/EEA
Date on which this record was first entered in the EudraCT database: 2018-10-18
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-003426-89/3rd/

A. Protocol Information
A.2 EudraCT number: 2018-003426-89
A.3 Full title of the trial: A Double-blind, Placebo-controlled Comparative Study and Open-label Extension Study to Confirm the Efficacy and Safety of E2020 in Subjects With Down Syndrome Having Regression Symptoms and Disabled Activities of Daily Living
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language: A Study to Confirm the Efficacy and Safety of E2020 in Subjects With Down Syndrome Having Regression Symptoms and Disabled Activities of Daily Living
A.4.1 Sponsor's protocol code number: E2020-J081-345
A.5.2 US NCT (ClinicalTrials.gov registry) number: NCT02094053
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan: 

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: Eisai Co., Ltd. (Japan)
B.1.3.4	Country: Japan
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 Co., Ltd.
B.5.2 Functional name of contact point: Customer Joy Department EJ
B.5.3 Address
B.5.3.1 Street Address: Koishikawa 4-6-10
B.5.3.2 Town/ city: Bunkyo-ku, Tokyo
B.5.3.3 Post code: 1128088
B.5.3.4 Country: Japan
B.5.4 Telephone number: 81120161454
B.5.6 E-mail: eisai-chiken_hotline@hhc.eisai.co.jp

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: Donepezil hydrochloride
D.3.2 Product code: E2020
D.3.4 Pharmaceutical form: Granules
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Oral use
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
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: Granules
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, regression symptoms and disabled activities of daily living
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: No
E.2 Objective of the trial
E.2.1 Main objective of the trial: To investigate dose-response of E2020 in change of the total score of the Body Functionality Checklist (psychosomatic function questionnaire) from baseline relative to placebo in subjects with Down syndrome who have regression symptoms and disabled activities of daily living.
E.2.2 Secondary objectives of the trial: To evaluate safety of E2020 compared to placebo as the control and pharmacokinetics of E2020 in subjects with Down syndrome who have regression symptoms and disabled activities of daily living and to evaluate safety of E2020 during long-term treatment in subjects who completed the Double-Blind Phase.
E.2.3 Trial contains a sub-study: No
E.3 Principal inclusion criteria: At enrollment in Pre-randomization Phase
1.   With definitive diagnosis of Down syndrome
2.   Have greater than or equal to 3 of the following 4 symptoms among 9 items according to the diagnostic criteria issued by the Intractable Diseases Treatment Research Program 2010 (Research paper on Intractable Diseases Treatment Research Program; Survey on Sudden Regression (21 trisomy) and Preparation of Diagnostic Criteria.) Motor retardation, mutism, social withdrawal (homeboundness), sleep disorder
3.   Insufficiently improved with environmental adjustment and psychotherapies including counseling for greater than or equal to 8 weeks before enrollment
4.   A total score of Body Functionality Checklist (51 items) is lesser than or equal to 210 at enrollment
5.   Aged 15 to 39 years inclusive
6.   Males and females
7.   Must have a family member or a caregiver who will provide written informed consent and will be able to spend 3 days a week with the subject (at least 4 hours per day) and will be able to support the subject during the study by providing necessary study information to the subject, assisting treatment compliance, and accompanying the subject to all scheduled visits, supporting study-related tests for the efficacy and safety assessments throughout the study period
8.   Males and females of childbearing potential must practice highly effective contraception
9.   Able to comply with scheduled study visits according to the investigator’s instruction
10.   Able to visit for scheduled assessments (except for walking difficulty due to development of regression)
11.   Submitted written informed consent for study entry (to obtain from subjects as much as possible; mandatory from their legal guardian)
E.4 Principal exclusion criteria: At enrollment in Pre-randomization Phase
1.   Suspected to have progressive neuropsychiatric disease (e.g., neurodegenerative disorder and progressive tumor) evidenced by MRI or CT within 1 year before the Pre-randomization Phase (if not tested within 1 year before the Pre-randomization Phase, reconfirm during the Pre-randomization Phase).
2.   Have a history of significant neurological disorders such as stroke, brain tumor, encephalitis, meningitis, normal pressure hydrocephalus, brain trauma accompanying unconsciousness, and experience of brain surgery causing unsolved deficiency
3.   Previously diagnosed with autism
4.   With evidence of atlantoaxial subluxation, or underwent surgical operation for atlantoaxial subluxation within 2 years
5.   Have seizure symptoms within 2 years or used antiepileptic drug within 1 year before enrollment of Pre-randomization Phase.
6.   With severe hearing or visual impairment which may affect regression
7.   Have a complication of cardiac disease (angina pectoris, congestive heart failure, bundle branch block, arrythmia) or peripheral vascular disease with unstable condition in 3 months before enrollment of Pre-randomization Phase
8.   Have a complication of clinically significant active and unstable diseases in the gastrointestinal, hepatic, renal, respiratory, or cardiovascular system
9.   Have a history of clinically significant gastrointestinal ulcer, bronchial asthma, or obstructive pulmonary disease
10.   Have a complication of disease affecting absorption, distribution, and metabolism of study drug (e.g., inflammatory colon disease, gastric ulcer, duodenal ulcer, hepatic disorder, serious lactose intolerance)
11.   With a present or past history of malignant tumor within 5 years before informed consent (except for basal cell carcinoma, squamous cell carcinoma)
12.   With a complication or history of drug or alcohol dependency within recent 10 years
13.   Have a known hypersensitivity to ingredient(s) of donepezil hydrochloride or peperidine derivatives
14.   Not meet the criteria of prohibited and restricted concomitant medications, or anticipated to deviate from the above criteria of prohibited and restricted concomitant medications/therapies during the study
15.   Pregnant or lactating women
16.   Have participated in another clinical study and received the study drug within 12 weeks before the enrollment of this study
17.   Have used donepezil hydrochloride or have participated in a clinical study of E2020 and received E2020 in the past
18.   With a history of a treatment for Alzheimer’s type dementia
19.  With severe extrapyramidal disorder
At enrollment in the Double-blind Phase
20.   Suspected to have a complication of severe disease considering from the laboratory parameters at enrollment in the Pre-randomization Phase (visit 1) and the safety is not protected in the opinion of the principal investigator or subinvestigator
E.5 End points
E.5.1 Primary end point(s): Change from Baseline (Week 0) in total scores using Body Functionality Checklist (psychosomatic function questionnaire) in subjects with Down syndrome having regression symptoms and disabled activities of daily living (ADL), relative to placebo at Week 24
E.5.1.1 Timepoint(s) of evaluation of this end point: Baseline (Week 0) and Week 24
E.5.2 Secondary end point(s): 1) Change from Baseline (Week 0) in total scores using Body Functionality Checklist (psychosomatic function questionnaire) in subjects with Down syndrome having regression symptoms and disabled activities of daily living (ADL), relative to placebo at Week 4 and 12

2) Change from Baseline (Week 0) in Timed Up and Go (TUG) Test at Week 24
 
3) Number of Subjects with Overall Improvement in the Clinical Global Impression of Change (CGIC) at Week 12 and 24

4) Safety of E2020 and Placebo in Subjects with Down Syndrome Having Regression and Disabled ADL 

5) Pharmacokinetics (PK) of E2020 and Placebo in Subjects with Down Syndrome Having Regression and Disabled ADL
E.5.2.1 Timepoint(s) of evaluation of this end point: 1) Baseline (Week 0), Week 4 and 12

2) Baseline (Week 0) and Week 24

3) Week 12 and 24

4) Up to Week 28

5) Up to Week 28
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: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
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): Yes
E.7.3 Therapeutic confirmatory (Phase III): No
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: No
E.8.2.4 Number of treatment arms in the trial: 3
E.8.3 Will this trial be conducted at a single site globally?: No
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:
Japan
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.8.9.2 In all countries concerned by the trial years: 3
E.8.9.2 In all countries concerned by the trial months: 7
E.8.9.2 In all countries concerned by the trial days: 3

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: 60
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): Yes
F.1.1.6.1 Number of subjects for this age range: 60
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 60
F.1.3 Elderly (>=65 years): No
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: No
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: No
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
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: 60
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: Japan