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.
Primary Purpose
Down Syndrome
Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
E2020-Donepezil hydrochloride
E2020-Donepezil hydrochloride
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Down Syndrome focused on measuring Down syndrome, regression symptoms, disabled activities of daily living
Eligibility Criteria
Inclusion Criteria
At enrollment in Pre-randomization Phase
- With definitive diagnosis of Down syndrome
- 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
- Insufficiently improved with environmental adjustment and psychotherapies including counseling for greater than or equal to 8 weeks before enrollment
- Have a suspected diagnosis with neuropsychiatric disorder without sufficient effect on a disease even after medical treatment for greater than or equal to 8 weeks before enrollment.
- A total score of Body Functionality Checklist (51 items) is lesser than or equal to 210 at enrollment
- Aged 15 to 39 years inclusive
- Males and females
- 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
- Males and females of childbearing potential must practice highly effective contraception
- Able to comply with scheduled study visits according to the investigator's instruction
- Able to visit for scheduled assessments (except for walking difficulty due to development of regression)
- Submitted written informed consent for study entry (to obtain from subjects as much as possible; mandatory from their legal guardian)
Exclusion Criteria
At enrollment in Pre-randomization Phase
- 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).
- 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
- Previously diagnosed with autism
- With evidence of atlantoaxial subluxation, or underwent surgical operation for atlantoaxial subluxation within 2 years
- Have seizure symptoms within 2 years or used antiepileptic drug within 1 year before enrollment of Pre-randomization Phase.
- With severe hearing or visual impairment which may affect regression
- 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
- Have a complication of clinically significant active and unstable diseases in the gastrointestinal, hepatic, renal, respiratory, or cardiovascular system
- Have a history of clinically significant gastrointestinal ulcer, bronchial asthma, or obstructive pulmonary disease
- 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)
- With a present or past history of malignant tumor within 5 years before informed consent (except for basal cell carcinoma, squamous cell carcinoma)
- With a complication or history of drug or alcohol dependency within recent 10 years
- Have a known hypersensitivity to ingredient(s) of donepezil hydrochloride or peperidine derivatives
- 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
- Pregnant or lactating women
- Have participated in another clinical study and received the study drug within 12 weeks before the enrollment of this study
- Have used donepezil hydrochloride or have participated in a clinical study of E2020 and received E2020 in the past
- With a history of a treatment for Alzheimer's type dementia
With severe extrapyramidal disorder
At enrollment in the Double-blind Phase
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
E2020 3 mg
E2020 5 mg
Placebo
Arm Description
3 mg of E2020 (oral) once daily, for 24 weeks
5 mg of E2020 (oral) once daily, for 24 weeks
placebo (oral) once daily, for 24 weeks
Outcomes
Primary Outcome Measures
Changes in total scores from baseline 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.
For the changes in a total score of Body Functionality Checklist (51 items) from Week 0 of the treatment period, Kruskal-Wallis test will be performed in the 3 mg group, the 5 mg group and placebo group to represent statistical significance. Summary statistics of the total score of Body Functionality Checklist (51 items) at each evaluation time and changes from before study drug administration in the treatment period will be calculated by dose group.
Secondary Outcome Measures
Safety of E2020 and placebo in subjects with Down syndrome having regression and disabled ADL.
The safety will be measured by frequencies of treatment-emergent adverse events (TEAEs) in the treatment period, statistics of laboratory parameters, blood pressure, and pulse rate at each evaluation time and changes from before study drug administration, and 12-lead ECG assessment, frequency distribution (yes/no) at each evaluation time will be collected and the percent (%) will be calculated by dose group.
Pharmacokinetics (PK) of E2020 and placebo in subjects with Down syndrome having regression and disabled ADL
Population PK analysis will be performed to build PK models to explain plasma donepezil hydrochloride concentration data. In addition, the models may be used to explore relationship of PK data with demographics, efficacy, and AEs.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02094053
Brief Title
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.
Official Title
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.
Study Type
Interventional
2. Study Status
Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
September 12, 2013 (Actual)
Primary Completion Date
September 16, 2016 (Actual)
Study Completion Date
April 21, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Co., Ltd.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this double-blind, placebo-controlled, comparative study and open-label extension study is to confirm the efficacy and safety of E2020 in subjects with Down syndrome having regression symptoms and disabled activities of daily living.
Detailed Description
This is a multicenter, randomized, double-blind, multiple-dose (two doses), placebo-controlled, parallel-group comparative study followed by an open-label extension study of E2020 in subjects with Down syndrome having regression and disabled ADL. A total of 60 subjects will be randomized to one of three dosing groups (at 1:1:1) to receive 3 mg of E2020, 5 mg of E2020, or placebo for 24 weeks based on their total scores of Body Functionality Checklist, sex, and study site as the allocation factors. This study consists of Pre-randomization Phase (4 weeks), Double-blind Phase (28 weeks), and Extension Phase (24 weeks). The Double-blind Phase includes a 24-week treatment period plus a 4-week transition period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Down Syndrome
Keywords
Down syndrome, regression symptoms, disabled activities of daily living
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
E2020 3 mg
Arm Type
Experimental
Arm Description
3 mg of E2020 (oral) once daily, for 24 weeks
Arm Title
E2020 5 mg
Arm Type
Experimental
Arm Description
5 mg of E2020 (oral) once daily, for 24 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
placebo (oral) once daily, for 24 weeks
Intervention Type
Drug
Intervention Name(s)
E2020-Donepezil hydrochloride
Intervention Description
3 mg of E2020 (oral) once daily, for 24 weeks
Intervention Type
Drug
Intervention Name(s)
E2020-Donepezil hydrochloride
Intervention Description
5 mg of E2020 (oral) once daily, for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo (oral) once daily, for 24 weeks
Primary Outcome Measure Information:
Title
Changes in total scores from baseline 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.
Description
For the changes in a total score of Body Functionality Checklist (51 items) from Week 0 of the treatment period, Kruskal-Wallis test will be performed in the 3 mg group, the 5 mg group and placebo group to represent statistical significance. Summary statistics of the total score of Body Functionality Checklist (51 items) at each evaluation time and changes from before study drug administration in the treatment period will be calculated by dose group.
Time Frame
Baseline to Week 12 and Week 24
Secondary Outcome Measure Information:
Title
Safety of E2020 and placebo in subjects with Down syndrome having regression and disabled ADL.
Description
The safety will be measured by frequencies of treatment-emergent adverse events (TEAEs) in the treatment period, statistics of laboratory parameters, blood pressure, and pulse rate at each evaluation time and changes from before study drug administration, and 12-lead ECG assessment, frequency distribution (yes/no) at each evaluation time will be collected and the percent (%) will be calculated by dose group.
Time Frame
Up to Week 28
Title
Pharmacokinetics (PK) of E2020 and placebo in subjects with Down syndrome having regression and disabled ADL
Description
Population PK analysis will be performed to build PK models to explain plasma donepezil hydrochloride concentration data. In addition, the models may be used to explore relationship of PK data with demographics, efficacy, and AEs.
Time Frame
Up to Week 28
10. Eligibility
Sex
All
Minimum Age & Unit of Time
15 Years
Maximum Age & Unit of Time
39 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
At enrollment in Pre-randomization Phase
With definitive diagnosis of Down syndrome
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
Insufficiently improved with environmental adjustment and psychotherapies including counseling for greater than or equal to 8 weeks before enrollment
Have a suspected diagnosis with neuropsychiatric disorder without sufficient effect on a disease even after medical treatment for greater than or equal to 8 weeks before enrollment.
A total score of Body Functionality Checklist (51 items) is lesser than or equal to 210 at enrollment
Aged 15 to 39 years inclusive
Males and females
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
Males and females of childbearing potential must practice highly effective contraception
Able to comply with scheduled study visits according to the investigator's instruction
Able to visit for scheduled assessments (except for walking difficulty due to development of regression)
Submitted written informed consent for study entry (to obtain from subjects as much as possible; mandatory from their legal guardian)
Exclusion Criteria
At enrollment in Pre-randomization Phase
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).
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
Previously diagnosed with autism
With evidence of atlantoaxial subluxation, or underwent surgical operation for atlantoaxial subluxation within 2 years
Have seizure symptoms within 2 years or used antiepileptic drug within 1 year before enrollment of Pre-randomization Phase.
With severe hearing or visual impairment which may affect regression
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
Have a complication of clinically significant active and unstable diseases in the gastrointestinal, hepatic, renal, respiratory, or cardiovascular system
Have a history of clinically significant gastrointestinal ulcer, bronchial asthma, or obstructive pulmonary disease
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)
With a present or past history of malignant tumor within 5 years before informed consent (except for basal cell carcinoma, squamous cell carcinoma)
With a complication or history of drug or alcohol dependency within recent 10 years
Have a known hypersensitivity to ingredient(s) of donepezil hydrochloride or peperidine derivatives
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
Pregnant or lactating women
Have participated in another clinical study and received the study drug within 12 weeks before the enrollment of this study
Have used donepezil hydrochloride or have participated in a clinical study of E2020 and received E2020 in the past
With a history of a treatment for Alzheimer's type dementia
With severe extrapyramidal disorder
At enrollment in the Double-blind Phase
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
Facility Information:
City
Fukuoka-shi
State/Province
Fukuoka
Country
Japan
City
Sapporo-shi
State/Province
Hokkaido
Country
Japan
City
Yokohama-shi
State/Province
Kanagawa
Country
Japan
City
Takatsuki-shi
State/Province
Kyoto
Country
Japan
City
Matsumoto-shi
State/Province
Nagano
Country
Japan
City
Nagasaki-shi
State/Province
Nagasaki
Country
Japan
City
Izumi-shi
State/Province
Osaka
Country
Japan
City
Saitama-shi
State/Province
Saitama
Country
Japan
City
Chiyoda-ku
State/Province
Tokyo
Country
Japan
City
Setagaya-ku
State/Province
Tokyo
Country
Japan
12. IPD Sharing Statement
Learn more about this 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.
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