Clinical Trial Results:
A Placebo-Controlled, Double-Blind, Parallel-Group, 24 Month Study With an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Subjects With Early Alzheimer’s Disease
Summary
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EudraCT number |
2016-003928-23 |
Trial protocol |
GB ES CZ AT BG GR FR |
Global end of trial date |
15 Jan 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Dec 2023
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First version publication date |
30 Jan 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
E2609-G000-301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02956486 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND Number: 109308 | ||
Sponsors
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Sponsor organisation name |
Eisai Ltd.
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Sponsor organisation address |
Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN
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Public contact |
Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com
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Scientific contact |
Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Jan 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Jan 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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)
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Protection of trial subjects |
This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008). - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312. - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Oct 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 71
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Country: Number of subjects enrolled |
Spain: 101
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Country: Number of subjects enrolled |
United Kingdom: 154
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Country: Number of subjects enrolled |
Austria: 7
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Country: Number of subjects enrolled |
Bulgaria: 19
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Country: Number of subjects enrolled |
Czech Republic: 65
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Country: Number of subjects enrolled |
France: 54
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Country: Number of subjects enrolled |
Germany: 51
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Country: Number of subjects enrolled |
Greece: 15
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Country: Number of subjects enrolled |
China: 64
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Country: Number of subjects enrolled |
Croatia: 9
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Country: Number of subjects enrolled |
Hungary: 9
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Country: Number of subjects enrolled |
Russian Federation: 3
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Country: Number of subjects enrolled |
Slovakia: 38
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Country: Number of subjects enrolled |
Japan: 303
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Country: Number of subjects enrolled |
Canada: 49
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Country: Number of subjects enrolled |
United States: 823
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Country: Number of subjects enrolled |
Singapore: 11
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Country: Number of subjects enrolled |
Korea, Republic of: 84
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Country: Number of subjects enrolled |
Taiwan: 8
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Country: Number of subjects enrolled |
Argentina: 74
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Country: Number of subjects enrolled |
Chile: 17
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Country: Number of subjects enrolled |
Mexico: 4
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Country: Number of subjects enrolled |
Australia: 49
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Country: Number of subjects enrolled |
Denmark: 17
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Country: Number of subjects enrolled |
Finland: 4
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Country: Number of subjects enrolled |
Italy: 55
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Country: Number of subjects enrolled |
Portugal: 19
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Country: Number of subjects enrolled |
South Africa: 27
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Worldwide total number of subjects |
2204
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EEA total number of subjects |
688
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
341
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From 65 to 84 years |
1841
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85 years and over |
22
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Recruitment
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Recruitment details |
Subjects took part at 426 investigative sites in China,Bulgaria,Croatia,Czech Republic,Greece,Hungary,Poland,Russia,Slovakia,Japan,Canada,Singapore,South Korea,Taiwan,Argentina,Chile,Mexico,Australia,Austria,Denmark,Finland,France,Germany,Italy,Portugal,South Africa,Spain,United Kingdom and United States from 20 October 2016 to 15 January 2020. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
This study included 2 parts: Core Phase and Extension Phase. A total of 9758 subjects were screened, of which 7546 subjects were screen failures and 2212 subjects were randomized in the study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) was pooled. | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Core Phase
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Core Phase: Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.
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Arm title
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Core Phase: Elenbecestat 50 mg | |||||||||||||||||||||||||||||||||
Arm description |
Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Elenbecestat
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Investigational medicinal product code |
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Other name |
E2609
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.
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Period 2
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Period 2 title |
Extension Phase
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Arm title
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Extension Phase: Elenbecestat 50 mg | |||||||||||||||||||||||||||||||||
Arm description |
Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after the last dose of elenbecestat in the extension phase. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Elenbecestat
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Investigational medicinal product code |
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Other name |
E2609
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first (up to a maximum of 5 months). Subjects were followed up for 1 month after last dose of elenbecestat in extension phase.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only eligible subjects who completed core and consented for extension phase, entered extension phase. |
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Baseline characteristics reporting groups
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Reporting group title |
Core Phase: Placebo
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Reporting group description |
Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Core Phase: Elenbecestat 50 mg
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Reporting group description |
Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Core Phase: Placebo
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Reporting group description |
Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. | ||
Reporting group title |
Core Phase: Elenbecestat 50 mg
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Reporting group description |
Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase. | ||
Reporting group title |
Extension Phase: Elenbecestat 50 mg
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Reporting group description |
Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after the last dose of elenbecestat in the extension phase. |
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End point title |
Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score | ||||||||||||
End point description |
Clinical dementia rating(CDR)scale is a clinical global rating scale that requires interviewing both subject and informant who knows and has contact with subject.CDR scale:clinician directed assessment of both cognition and function, and is intended to capture state and therefore disease stage of subject.CDR scale:6 domains of subject function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3.CDR-SB:sum of individual domain scores and ranges from 0 to 18.Higher score indicates more impairment.FAS: group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.Subjects analyzed:all subjects included in mixed effects model for repeated measures (MMRM) who were evaluable this specific outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
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Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (mild cognitive impairment [MCI]/Prodromal, mild alzheimer’sdisease [AD]), concurrent AD medication use, region, apolipoprotein E (ApoE4) status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
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Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
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Number of subjects included in analysis |
2131
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.385 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Least Square (LS) Mean Difference | ||||||||||||
Point estimate |
-0.17
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.57 | ||||||||||||
upper limit |
0.22 |
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End point title |
Extension Phase: Number of Subjects Reporting One or More Treatment-emergent Adverse Events (TEAEs) [1] | ||||||
End point description |
A TEAE is defined as an adverse event that emerged during treatment or within 28 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event was continuous. Number of subjects with TEAEs (serious and non-serious adverse events) were reported based on their safety assessments of laboratory tests, suicidal ideation and suicidal behavior, drug abuse potential, physical examination, neurological examination, regular measurement of vital signs, magnetic resonance imaging and electrocardiogram parameter values. All safety subjects was the group of subjects who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to approximately 6 months (including 1 month follow up) for the extension phase
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Core Phase: Change From Baseline up to Month 24 in Alzheimer’s Disease Composite Score (ADCOMS) | ||||||||||||
End point description |
ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), the Mini Mental State Examination (MMSE), and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "subjects analyzed" signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
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Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
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Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
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Number of subjects included in analysis |
1999
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.345 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.02
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.06 | ||||||||||||
upper limit |
0.02 |
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End point title |
Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) | ||||||||||||
End point description |
Amyloid PET scan assesses cerebral amyloid load using 3 tracers (florbetapir, florbetaben and flutemetamol) which is standardized into centiloids for evaluation of AD. Centiloid values on centiloid scale is based on mean composite SUVR in cingulate, frontal, parietal and temporal cortexes using whole cerebellum as reference region. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. The pharmacodynamic (PD) analysis set was the group of subjects in the core phase who had sufficient PD data to derive at least 1 PD parameter. Here "subjects analyzed" signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
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Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
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Comparison groups |
Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
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Number of subjects included in analysis |
516
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-12.83
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-18.79 | ||||||||||||
upper limit |
-6.88 |
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End point title |
Core Phase: Change From Baseline up to Month 24 in the CDR-SB Score for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6 | ||||||||||||
End point description |
CDR scale: clinician directed assessment of both cognition and function, and is intended to capture state and disease stage of subject. CDR scale: 6 domains of subject function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. CDR-SB: sum of individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates ratio of tracer uptake in frontal cortex relative to cerebellum or ratio of tracer uptake in whole brain relative to cerebellum.FAS:group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.Subjects analyzed:all subjects included in MMRM who were evaluable for this specific outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
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Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
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Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
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Number of subjects included in analysis |
1281
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.316 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.23
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.67 | ||||||||||||
upper limit |
0.22 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the ADCOMS for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6 | ||||||||||||
End point description |
ADCOMS:weighted linear combination of 12 items from 3 existing clinical scales:ADAS-cog,MMSE,and CDR.Four items are from the ADAS-cog(A4[Delayed Word Recall],A7[Orientation],A8[Word Recognition],A11[Word Finding]);2 items are from the MMSE(M1[Orientation Time],M7[Drawing]);6 items are from the CDR(C1[Personal Care],C2[Community Affairs],C3[Home and Hobbies],C4[Judgment and Problem Solving],C5[Memory],C6[Orientation]).Composite score:derived from variables from 12 items,and ranges from 0 to 1.97,where higher score indicates worse performance.Amyloid PET scans allow in vivo assessment of cerebral amyloid load.SUVR indicates ratio of tracer uptake in frontal cortex relative to cerebellum or ratio of tracer uptake in whole brain relative to cerebellum.FAS:randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 postdose primary efficacy measurement.Subjects analyzed:all subjects in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1198
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.254 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.07 | ||||||||||||
upper limit |
0.02 |
|
|||||||||||||
End point title |
Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24 | ||||||||||||
End point description |
CDR scale:clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with subject.CDR scale is a clinician directed assessment of both cognition and function,and is intended to capture state and disease stage of subject. CDR scale:6 domains of subject function(memory,orientation,judgement and problem solving,community affairs,home and hobbies and personal care)on a 5-point scale in which no impairment=0,questionable impairment=0.5,mild impairment=1,moderate impairment=2 and severe impairment=3.CDR-SB:sum of individual domain scores and ranges from 0 to 18.Higher score indicates more impairment.In this outcome measure,change per year(mean slope)in CDR-SB score was calculated up to month 24,where higher change indicated more impairment and lower change indicated less impairment.FAS:group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Based on the linear mixed effects model, which included assessment time and treatment group by assessment time interaction as covariate with random intercept and slope.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
2146
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9088 | ||||||||||||
Method |
Linear mixed effects model | ||||||||||||
Parameter type |
Difference of Mean Slope | ||||||||||||
Point estimate |
-0.008
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.145 | ||||||||||||
upper limit |
0.129 |
|
|||||||||||||
End point title |
Core Phase: Time to Worsening of CDR Score up to Month 24 | ||||||||||||
End point description |
CDR scale:requires interviewing both the subject and an informant who knows and has contact with the subject.CDR scale:clinician directed assessment of both cognition and function,and is intended to capture state and disease stage of subject. CDR scale assesses 6 domains of subject function(memory,orientation,judgement and problem solving,community affairs,home and hobbies and personal care)on a 5-point scale in which no impairment=0,questionable impairment=0.5,mild impairment=1,moderate impairment=2 and severe impairment=3.The global CDR score is computed via an algorithm and ranges from 0 to 3.Higher score indicates more impairment.In this outcome measure,time(in months)to worsening of CDR score(that is, an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits)up to month 24 was calculated.FAS:randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post dose primary efficacy measurement.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Based on a Cox regression model which included treatment group, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
2146
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.6155 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.95
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.77 | ||||||||||||
upper limit |
1.16 |
|
|||||||||||||
End point title |
Core Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 24 | ||||||||||||
End point description |
Time (in months) to conversion to dementia for subjects who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis). The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Based on a Cox regression model which included treatment group, concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1803
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1281 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.14
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.96 | ||||||||||||
upper limit |
1.35 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition14 (ADAS-Cog14) Score | ||||||||||||
End point description |
ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0-10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The total score ranges from 0 to 90. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1982
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.525 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.43
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.75 | ||||||||||||
upper limit |
0.9 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the MMSE Score | ||||||||||||
End point description |
MMSE:for screening purposes,staging of disease severity and measured in AD to follow disease progression and treatment effects.MMSE:composed of 30 questions grouped into domains(Orientation to Time[0-5], Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming[0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each of MMSE domains,six items are computed(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score(ranges 0 to 30)=sum of six domains.If any domain score is missing then total score is missing.Higher score indicates better function.FAS:Subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 postdose primary efficacy measurement.Subjects analyzed:signifies all subjects in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
|
||||||||||||
Number of subjects included in analysis |
2073
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.977 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.64 | ||||||||||||
upper limit |
0.62 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score | ||||||||||||
End point description |
FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The Total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity is missed, then the total score is missed. FAS: group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Subjects analyzed: all subjects included in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
2039
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.854 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.09 | ||||||||||||
upper limit |
1.32 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score | ||||||||||||
End point description |
The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
2055
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.314 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.27
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.79 | ||||||||||||
upper limit |
0.26 |
|
|||||||||||||
End point title |
Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition11 (ADAS-Cog11) Score | ||||||||||||
End point description |
ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total score ranges from 0 to 70. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1982
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.895 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.07
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.93 | ||||||||||||
upper limit |
1.07 |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the CDR-SB Score | ||||||||||||
End point description |
CDR scale: a clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with the subject. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the subject. The CDR scale assesses 6 domains of subject function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher scores indicates more impairment. FAS: group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1493
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.542 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.09 | ||||||||||||
upper limit |
0.17 |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the ADCOMS | ||||||||||||
End point description |
ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.38 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.02 | ||||||||||||
upper limit |
0.01 |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the ADAS-cog11 Score | ||||||||||||
End point description |
ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total score ranges from 0 to 70. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.063 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.82 | ||||||||||||
upper limit |
0.02 |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the ADAS-cog14 Score | ||||||||||||
End point description |
ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total Score ranges from 0 to 90. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
|
||||||||||||
Number of subjects included in analysis |
1326
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.045 [2] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.56
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.11 | ||||||||||||
upper limit |
-0.01 | ||||||||||||
Notes [2] - Based on a MMRM, which included baseline as a covariate with treatment groups as fixed effects. |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the MMSE Score | ||||||||||||
End point description |
MMSE:instrument used for screening purposes,staging of disease severity and measured longitudinally in AD to follow disease progression/treatment effects.MMSE:composed of 30 questions grouped into domains(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming[0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each MMSE domains,six items are computed(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score(ranges from 0 to 30)=sum of six domains.If any domain score is missing then total score is missing.Higher score indicates better function.FAS:Subjects who received at least 1 dose of drug and had baseline and at least 1 post-dose primary efficacy measurement."Subjects analyzed"signifies subjects evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1453
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.799 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.32 | ||||||||||||
upper limit |
0.24 |
|
|||||||||||||
End point title |
Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score | ||||||||||||
End point description |
The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Core Phase: Placebo,Core Phase: Elenbecestat 50 mg | ||||||||||||
Statistical analysis description |
Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
|
||||||||||||
Comparison groups |
Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
|
||||||||||||
Number of subjects included in analysis |
1392
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.012 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.32
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.56 | ||||||||||||
upper limit |
-0.07 |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score | ||||||||
End point description |
The CDR scale is a clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with the subject. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the subject. The CDR scale assesses 6 domains of subject function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [3] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS | ||||||||
End point description |
ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [4] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score | ||||||||
End point description |
MMSE: cognitive instrument used for screening purposes,staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects.MMSE: 30 questions grouped into domains(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming [0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each of MMSE domains, six items are computed(Orientation to Time[0-5],Orientation to Place [0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score:sum of six domains and ranges from 0 to 30.If any domain score is missing then total score is missing.Higher score indicates better function.Data:not reported as study terminated prior to reaching specified time point.Statistical analysis plan:modified to indicate that extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [5] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score | ||||||||
End point description |
FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as follows: 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity is missed, then the total score is missed. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [6] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score | ||||||||
End point description |
ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The total score ranges from 0 to 90. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [7] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score | ||||||||
End point description |
The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [8] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Extension Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 12 of the Extension Phase | ||||||||
End point description |
Time (in months) to conversion to dementia for subjects who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis). Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
|
||||||||
|
|||||||||
Notes [9] - No subjects were analysed for this outcome measure. |
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
From first dose of study drug up to approximately 27 months (including 3 months follow up) for the Core Phase and up to approximately 6 months (including 1 month follow up) for the Extension Phase
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Core Phase: adverse events were reported for SAS (group of subjects who received at least 1 dose of drug and had at least 1 post-dose safety assessment). Extension Phase: adverse events were reported for All Safety Subjects analysis set: group of subjects who enrolled into extension phase and received at least 1 dose of drug in extension phase.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Core Phase: Placebo
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Reporting group description |
Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Core Phase: Elenbecestat 50 mg
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Reporting group description |
Subjects received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Extension Phase: Elenbecestat 50 mg
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Reporting group description |
Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after last dose of elenbecestat in extension phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Nov 2016 |
Amendment 01 to study E2609-G000-301 (2016-003928-23):
-Added that randomization was stratified according to region, disease status, and use of concomitant medications. Randomization was no longer to be stratified by
apolipoprotein E (ApoE) genotype.
-Added the requirement for central reading of ECG recordings for consistency.
-Added a secondary objective to determine whether elenbecestat was superior to placebo on the ADAS-cog14 Word List (immediate recall and delayed recall) at 24 months in subjects with EAD.
-Added a secondary objective to determine whether elenbecestat was superior to placebo on the change from baseline in CDR-SB at 27 months (ie, 24 months of treatment plus 3 months posttreatment follow-up).
-Additional instructions were provided regarding temporary suspension of study drug following lymphocytopenia and subsequent rechallenge.
-Administration of the Modified Hachinski Scale was moved to Tier 1 instead of Tier 2 to identify those subjects with vascular dementia and exclude them earlier in the screening process.
-Addition of sleep/dream questionnaire for subjects reporting AEs of abnormal dreams, nightmares or sleep terrors.
-Added requirement to measure absolute lymphocyte count (ALC) every 4 weeks for subjects who had a Grade 2 or greater lymphocytopenia during the follow-up period.
-Clinical chemistry and hematology test were made mandatory at the second Follow-up Visit.
-Added clarification regarding testing of blood samples for immunological assessments.
- Malignant neoplasms within 5 years of Screening were excluded from the study (changed from 3 years).
- Clarified that subjects who were illiterate were excluded from participation in the study.
- Additional blood samples for PD evaluation were added at follow up. |
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06 Feb 2017 |
Amendment 02 to study E2609-G000-301 (2016-003928-23) and amendment 01 to study E2609-G000-302 (2016-004128-42):
-Added China to the list of regions to participate in the study and changed the number of levels of stratification by region from 6 to 7 (added by Amendment 02 to Study 301 only: China was already included in Study 302).
-Added an exclusion for moderate to severe hepatic impairment and provided specific criteria.
-Prothrombin time and International Normalized Ratio (INR) (derived from prothrombin time) were added as a required part of Screening.
-Added that subjects who developed moderate to severe hepatic impairment during the study were to discontinue study drug.
-Removed exclusion of subjects undergoing lumbar puncture (LP) procedure with a medical condition with bleeding risk that is not under adequate control and provided
additional guidance for subjects receiving concomitant anticoagulation/antiplatelet therapy. These subjects were to have prothrombin time and INR prior to CSF LP; if they were assessed by the investigator to be at risk for bleeding, they were to be excluded from CSF collection.
-Added clarification to the exclusion criteria to specify that ALC was derived from the complete blood count with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they were present) and calculated by the white blood cell count × percentage of lymphocytes.
-Added that subjects who were assessed by both amyloid PET and CSF were required to wait for a minimum of 48 hours between the 2 procedures and deleted that CSF must be collected before PET assessment.
-Completion of the Sleep/Dream Questionnaire when triggered by AEs related to abnormal dreams, nightmares, or sleep terror was added for all study visits.
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04 Apr 2017 |
Amendment 03 to study E2609-G000-301 (2016-003928-23) and amendment 02 to study E2609-G000-302 (2016-004128-42):
-Added that start of open-label Extension Phase would require a protocol amendment with prior approval from applicable Health Authorities.
-Added that the end of the study for the double-blind Randomization Phase would be the date of the last study visit (Visit 15) for the last subject in the double-blind
Randomization Phase.
-Extended the requirement of compliance with local standard of care for concomitant use of AChEI or memantine for symptomatic treatment of AD to include initiation or changing dose of AChEI or memantine during the study.
-Revised the description of blood/CSF collection and assay for PD and exploratory biomarkers.
-Specified that PBMCs were to be stored for testing as required.
-Added that subjects who develop seizures were to be discontinued from study drug.
-Defined severe infection as follows: sepsis; deep tissue (invasive) infection; any infection requiring intravenous (IV) antibiotics; any infection requiring hospitalization (if outpatient at onset); any infection leading to need for oxygen, pressors or fluids to support blood pressure (BP), or intubation; any infection that requires major surgical intervention; pseudomembranous colitis due to C. difficile; typhlitis; osteomyelitis; and meningitis.
-Added guidance to action to be taken with drug administration for subjects who developed severe infections.
-Revised study drug interruption and discontinuation criteria for skin rash and herpes infections. Added instructions for drug consultation with medical monitor and potential rechallenge.
-Corrected description for calculating immediate memory score on ADAS-cog14.
-Added measurement of prothrombin time, INR (derived from prothrombin time), and activated partial thromboplastin time to each study visit.
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28 Jun 2017 |
Amendment 04 to study E2609-G000-301 (2016-003928-23) and amendment 03 to study E2609-G000-302 (2016-004128-42):
-Specified the duration of the Prerandomization Phase and that randomization was to occur no more than 10 days after completion of all screening Added that for any given subject, every effort was to be made to ensure that the diagnosing clinician (responsible for the initial diagnosis and for disease staging) and the CDR rater remained unchanged throughout the study.
-Removed PD blood specimen collection from the Screening Period and stipulated that Baseline blood draws for PD assessment were to be performed predose at Visit 2 (Randomization Phase) rather than during Screening.
-Specified that safety assessments of immune status were to be performed throughout the study.
-Specified that the MMSE and CDR requirements are to be met at Screening.
-Listed CSF Aβ(1-42) and tau:Aβ (1-42) ratio as examples of AD biomarkers for brain amyloid pathology.
-Added that PET scans performed at the ED Visit should only be performed if 6 months has elapsed since the prior PET scan.
-Specified that historical PET scans must have been positive for amyloid in order to be considered for eligibility purposes.
-Added that subjects must have the capacity to provide informed consent (as determined in accordance with applicable professional standards and local laws/regulations) to enroll in the study.
-Added that the study partner must be literate.
-Specified that findings of “diffuse” white matter disease “as defined by a score of 3 on the age-related white matter changes score” on centrally read brain MRI scan at Screening were exclusionary. Clarified that evidence of multiple lacunar infarcts was exclusionary, regardless of region, whereas evidence of stroke was exclusionary when it involved a major vascular territory.
-Provided guidance for possible inclusion of subjects successfully treated for hepatitis C.
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19 Jul 2018 |
Amendment 05 to study E2609-G000-301 (2016-003928-23) and Amendment 04 to study E2609-G000-302 (2016-004128-42):
-An optional tau PET longitudinal substudy was added for study eligible subjects from select geographical sites in the US (based on the proximity to the tau PET ligand manufacturing sites) that have had an amyloid positive study specific PET scan and consented to participate in the optional amyloid PET longitudinal substudy. |
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21 Jan 2019 |
Amendment 06 to study E2609-G000-301 (2016-003928-23) and Amendment 05 to study E2609-G000-302 (2016-004128-42):
-Added details for the open-label Extension Phase.
-Added the plan for pooling of Studies 301 and 302 analysis, with decreased subjects and sites in each study.
-Key secondary objectives were defined among the multiple secondary objectives, indicating those of most importance that were tested in a hierarchical manner.
-Added Alzheimer's Disease Composite Score (ADCOMS) as a secondary objective for the Core Studies.
-Added of CDR-SB and ADCOMS enriched by baseline amyloid PET standardized uptake value ratio (SUVR) as a secondary objective for the Core Studies.
-Added a biomarker objective and endpoints for the Core Studies.
-Revised the country list to reflect that South Africa was a participating country.
-Added that if subjects had non MRI compatible devices fitted during treatment, then a computed tomography scan could be utilized to assess safety, if deemed appropriate by the investigator.
-Added that CSF was to be used to assess PD, PK, and exploratory biomarkers.
-Added that CSF and PET assessments were to be conducted before any other visit assessments and while the study was still study drug
-Added that new AEs were to be collected for 4 weeks post last dose and followed-up for 12 weeks, or until resolution, whichever came first. AEs relating to study procedures were to be collected until the end of study participation.
-Allowed for historical CSF samples, if collected, processed, and stored under appropriate conditions and approved by the sponsor, to be analyzed to determine CSF amyloid positivity.
-Added that levels of Vitamin B12 may be confirmed with reflex testing to include methylmalonic acid analysis, if available in region.
-Revised exclusion criterion to specify that if the QTcF machine read was greater than 440 ms on the first single 12-lead ECG, 2 additional 12-lead ECGs were to be performed.
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23 May 2019 |
Amendment 07 to study E2609-G000-301 (2016-003928-23) and Amendment 06 to study E2609-G000-302 (2016-004128-42):
-To comply with applicable professional standards and local laws/regulations, added that subjects in Japan who lost the capacity to provide informed consent during the Core Studies were eligible for inclusion in the Extension Phase if the investigators obtain subject assent and consent of the legal representative. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Study terminated early due to unfavorable risk-benefit ratio including no evidence of potential efficacy and adverse event profile with drug was worse than placebo.Small sample size at 24 month timepoint of core phase limits interpretability of data. |