A 24-Month Study to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Participants With Early Alzheimer's Disease (MissionAD1)

• ClinicalTrials.gov Identifier: NCT02956486
• Recruitment Status: Terminated
• First Posted: November 6, 2016
• Results First Posted: February 3, 2021
• Last Update Posted: February 3, 2021
• Sponsor: Eisai Co., Ltd.
• Collaborator: Biogen
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Co., Ltd. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease
• Interventions: Drug: Elenbecestat; Drug: Placebo
• Enrollment: 2212

Participant Flow

Recruitment Details	Participants took part in the study 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 the United States from 20 October 2016 to 15 January 2020.
Pre-assignment Details	This study included 2 parts: Core Phase and Extension Phase. A total of 9758 participants were screened, of which 7546 participants were screen failures and 2212 participants were randomized in the study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) was pooled.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg	Extension Phase: Elenbecestat 50 mg
Arm/Group Description	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.	Eligible participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Period Title: Core Phase
Started	1108	1104	0
Treated	1108	1101	0
Safety Analysis Set (SAS)	1105	1099	0
Full Analysis Set (FAS)	1084	1062	0
Completed	29	32	0
Not Completed	1079	1072	0
Reason Not Completed
Adverse Event	51	88	0
Lost to Follow-up	8	6	0
Inadequate therapeutic effect	4	5	0
Withdrawal by Subject	101	104	0
Study terminated by sponsor	888	848	0
Other	27	18	0
Not treated	0	3	0
Period Title: Extension Phase
Started	0	0	19 [1]
Treated	0	0	18
Safety Analysis Set (SAS)	0	0	18
Completed	0	0	0
Not Completed	0	0	19
Reason Not Completed
Adverse Event	0	0	2
Study terminated by sponsor	0	0	16
Not Treated	0	0	1
[1] Eligible participants who completed core and consented for extension phase, entered extension phase.

Baseline Characteristics

Arm/Group Title		Core Phase: Placebo	Core Phase: Elenbecestat 50 mg	Total
Arm/Group Description		Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.	Total of all reporting groups
Overall Number of Baseline Participants		1105	1099	2204
Baseline Analysis Population Description		The SAS was the group of participants who received at least 1 dose of study drug in the core phase and had at least 1 post-dose safety assessment.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1105 participants	1099 participants	2204 participants
		72.1 (7.09)	71.9 (7.18)	72.0 (7.13)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1105 participants	1099 participants	2204 participants
	Female	592 53.6%	534 48.6%	1126 51.1%
	Male	513 46.4%	565 51.4%	1078 48.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1105 participants	1099 participants	2204 participants
	Hispanic or Latino	162 14.7%	158 14.4%	320 14.5%
	Not Hispanic or Latino	943 85.3%	941 85.6%	1884 85.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1105 participants	1099 participants	2204 participants
	American Indian or Alaska Native	1 0.1%	0 0.0%	1 0.0%
	Asian	233 21.1%	247 22.5%	480 21.8%
	Native Hawaiian or Other Pacific Islander	0 0.0%	2 0.2%	2 0.1%
	Black or African American	12 1.1%	22 2.0%	34 1.5%
	White	851 77.0%	817 74.3%	1668 75.7%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	8 0.7%	11 1.0%	19 0.9%

Outcome Measures

1. Primary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score
Description	The clinical dementia rating (CDR) scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in mixed effects model for repeated measures (MMRM) who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1078	1053
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	2.17 (0.142)	1.99 (0.146)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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's disease [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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.385
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.22
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Extension Phase: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
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 participants 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.
Time Frame	From first dose of study drug up to approximately 6 months (including 1 month follow up) for the extension phase

Outcome Measure Data

Analysis Population Description

All safety participants was the group of participants who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	18
Measure Type: Count of Participants; Unit of Measure: Participants
	6 33.3%

3. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in Alzheimer's Disease Composite Score (ADCOMS)
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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1018	981
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.24 (0.014)	0.23 (0.015)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.345
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.02
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR)
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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The pharmacodynamic (PD) analysis set was the group of participants in the core phase who had sufficient PD data to derive at least 1 PD parameter. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	268	248
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	7.81 (2.500)	-5.02 (2.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.001
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-12.83
	Confidence Interval	(2-Sided) 95%; -18.79 to -6.88
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the CDR-SB Score for Participants Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6
Description	The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates the ratio of tracer uptake in the frontal cortex relative to the cerebellum or the ratio of tracer uptake in the whole brain relative to the cerebellum.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	664	617
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	1.97 (0.157)	1.74 (0.169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.316
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.67 to 0.22
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the ADCOMS for Participants Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6
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. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates the ratio of tracer uptake in the frontal cortex relative to the cerebellum or the ratio of tracer uptake in the whole brain relative to the cerebellum.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	627	571
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.23 (0.017)	0.20 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.254
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.02
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24
Description	The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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. 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.
Time Frame	Up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1084	1062
Least Squares Mean (95% Confidence Interval); Unit of Measure: change in score per year
	0.934; (0.838 to 1.030)	0.926; (0.828 to 1.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9088
	Comments	[Not Specified]
	Method	Linear mixed effects model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference of Mean Slope
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95%; -0.145 to 0.129
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Core Phase: Time to Worsening of CDR Score up to Month 24
Description	The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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.
Time Frame	Up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1084	1062
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [2]; (24.07 to NA)

[1]

Median and 95 percent (%) confidence interval (CI) could not be estimated due to the low number of participants with events.

[2]

Median and Upper limit of 95% CI could not be estimated due to the low number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6155
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.16
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Core Phase: Time to Conversion to Dementia for Participants Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 24
Description	Time (in months) to conversion to dementia for participants 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).
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	902	901
Median (95% Confidence Interval); Unit of Measure: months
	23.05; (21.14 to 24.66)	21.40; (20.45 to 24.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	Based on a Cox regression model which included treatment group, concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1281
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.35
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition14 (ADAS-Cog14) Score
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 participants. The total score ranges from 0 to 90. Higher score indicates more impairment.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1010	972
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	5.38 (0.490)	4.95 (0.520)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.525
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -1.75 to 0.90
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the MMSE Score
Description	The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is 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 the 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]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score was missing then the total score was missing. Higher score indicates better function.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1056	1017
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-2.87 (0.234)	-2.87 (0.241)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.977
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.64 to 0.62
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score
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 was missed, then the total score was missed. Activities rated as "Not Applicable" were not used in the computation of the total score. To account for "Not Applicable" activity, the total score was weighted as:Total Score=Total Score*30/(30 minus 3 times the number of activities marked"Not Applicable").
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1038	1001
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	5.20 (0.448)	5.32 (0.459)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.854
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -1.09 to 1.32
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
Description	The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants 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: Participants 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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1050	1005
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	1.63 (0.195)	1.36 (0.207)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.314
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.26
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition11 (ADAS-Cog11) Score
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 participants. The Total score ranges from 0 to 70. Higher score indicates more impairment.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	1010	972
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	4.11 (0.370)	4.18 (0.391)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.895
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.93 to 1.07
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Core Phase: Change From Last Dose in the CDR-SB Score
Description	The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	759	734
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.40 (0.045)	0.44 (0.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.542
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.17
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Core Phase: Change From Last Dose in the ADCOMS
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.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	666	646
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.06 (0.005)	0.06 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.380
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.01
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Core Phase: Change From Last Dose in the ADAS-cog11 Score
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 participants. The Total score ranges from 0 to 70. Higher score indicates more impairment.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	679	647
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.95 (0.150)	0.56 (0.153)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.063
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.82 to 0.02
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Core Phase: Change From Last Dose in the ADAS-cog14 Score
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 participants. The Total Score ranges from 0 to 90. Higher score indicates more impairment.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	679	647
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.96 (0.196)	0.40 (0.201)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.045
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -1.11 to -0.01
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Core Phase: Change From Last Dose in the MMSE Score
Description	The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is 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 the 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]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score was missing then the total score was missing. Higher score indicates better function.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	734	719
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-0.22 (0.101)	-0.26 (0.102)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.799
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.24
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
Description	The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants 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: Participants 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.
Time Frame	From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

Outcome Measure Data

Analysis Population Description

The FAS was the group of randomized participants 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 "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Core Phase: Placebo	Core Phase: Elenbecestat 50 mg
Arm/Group Description:	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.	Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
Overall Number of Participants Analyzed	707	685
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.54 (0.088)	0.22 (0.090)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.012
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.07
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score
Description	The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. 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 participant. The CDR scale assesses 6 domains of participant 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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

22. Secondary Outcome

Title	Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS
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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

23. Secondary Outcome

Title	Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score
Description	The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is 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 the 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]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score is missing then the total score is missing. Higher score indicates better function.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

24. Secondary Outcome

Title	Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score
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 was missed, then the total score was missed. Activities rated as "Not Applicable" were not used in the computation of the total score. To account for "Not Applicable" activity, the total score was weighted as:Total Score=Total Score*30/(30 minus 3 times the number of activities marked"Not Applicable").
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

25. Secondary Outcome

Title	Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score
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 participants. The total score ranges from 0 to 90. Higher score indicates more impairment.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

26. Secondary Outcome

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
Description	The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants 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: Participants 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.
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

27. Secondary Outcome

Title	Extension Phase: Time to Conversion to Dementia for Participants Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 12 of the Extension Phase
Description	Time (in months) to conversion to dementia for participants 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).
Time Frame	Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Extension Phase: Elenbecestat 50 mg
Arm/Group Description:	In the extension phase, participants 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. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	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 Description	In the Core Phase, adverse events were reported for the SAS (the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment). In the Extension Phase, adverse events were reported for the All Safety Participants analysis set: the group of participants who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.
Arm/Group Title	Core Phase: Placebo		Core Phase: Elenbecestat 50 mg		Extension Phase: Elenbecestat 50 mg
Arm/Group Description	Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.		Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.		Eligible participants 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. Participants were followed up for 1 month after last dose of elenbecestat in extension phase.
All-Cause Mortality
	Core Phase: Placebo		Core Phase: Elenbecestat 50 mg		Extension Phase: Elenbecestat 50 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	6/1105 (0.54%)		3/1099 (0.27%)		0/18 (0.00%)
Serious Adverse Events
	Core Phase: Placebo		Core Phase: Elenbecestat 50 mg		Extension Phase: Elenbecestat 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/1105 (10.59%)		134/1099 (12.19%)		0/18 (0.00%)
Blood and lymphatic system disorders
Anaemia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lymphadenopathy † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lymphopenia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cardiac disorders
Angina pectoris † 1	3/1105 (0.27%)	3	2/1099 (0.18%)	2	0/18 (0.00%)	0
Bradycardia † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Atrial fibrillation † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Tachycardia † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Acute myocardial infarction † 1	3/1105 (0.27%)	3	1/1099 (0.09%)	1	0/18 (0.00%)	0
Sinus node dysfunction † 1	2/1105 (0.18%)	2	1/1099 (0.09%)	1	0/18 (0.00%)	0
Angina unstable † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cardiac arrest † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Coronary artery stenosis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pericarditis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Myocardial infarction † 1	3/1105 (0.27%)	3	0/1099 (0.00%)	0	0/18 (0.00%)	0
Cardiac failure congestive † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Cardiomyopathy † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Coronary artery disease † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Mitral valve incompetence † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Paroxysmal atrioventricular block † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Sinus arrest † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Congenital, familial and genetic disorders
Type V hyperlipidaemia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Endocrine disorders
Thyroid mass † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Eye disorders
Cataract † 1	1/1105 (0.09%)	1	3/1099 (0.27%)	4	0/18 (0.00%)	0
Idiopathic orbital inflammation † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Retinal artery occlusion † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Diplopia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	3/1105 (0.27%)	3	1/1099 (0.09%)	1	0/18 (0.00%)	0
Inguinal hernia † 1	2/1105 (0.18%)	2	1/1099 (0.09%)	1	0/18 (0.00%)	0
Diarrhoea † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Diverticular perforation † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Duodenal ulcer haemorrhage † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Gastritis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Nausea † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Oesophageal spasm † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Small intestinal obstruction † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Umbilical hernia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Ascites † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Colitis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Pancreatitis acute † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Vomiting † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
General disorders
Non-cardiac chest pain † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Pyrexia † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Asthenia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Malaise † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Oedema peripheral † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pain † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	2	0/18 (0.00%)	0
Chills † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Hepatobiliary disorders
Hepatitis acute † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Autoimmune hepatitis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cholecystitis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cholecystitis acute † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Hepatic mass † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Infections and infestations
Pneumonia † 1	3/1105 (0.27%)	3	5/1099 (0.45%)	5	0/18 (0.00%)	0
Influenza † 1	2/1105 (0.18%)	2	5/1099 (0.45%)	5	0/18 (0.00%)	0
Urinary tract infection † 1	2/1105 (0.18%)	2	3/1099 (0.27%)	3	0/18 (0.00%)	0
Bronchitis † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Cellulitis † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Diverticulitis † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Subcutaneous abscess † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Sepsis † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Abscess limb † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Alpha haemolytic streptococcal infection † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Appendicitis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Atypical pneumonia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Bronchitis viral † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Colonic abscess † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Gastroenteritis viral † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lower respiratory tract infection viral † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lung infection † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pneumonia bacterial † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Gastroenteritis † 1	2/1105 (0.18%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Appendicitis perforated † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Campylobacter gastroenteritis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Enteritis infectious † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Erysipelas † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Febrile infection † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Infected skin ulcer † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Ophthalmic herpes zoster † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Osteomyelitis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Postoperative wound infection † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Pyelonephritis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Urosepsis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	4/1105 (0.36%)	4	7/1099 (0.64%)	7	0/18 (0.00%)	0
Hip fracture † 1	1/1105 (0.09%)	1	3/1099 (0.27%)	3	0/18 (0.00%)	0
Femur fracture † 1	0/1105 (0.00%)	0	3/1099 (0.27%)	3	0/18 (0.00%)	0
Head injury † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Rib fracture † 1	2/1105 (0.18%)	2	1/1099 (0.09%)	1	0/18 (0.00%)	0
Femoral neck fracture † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Spinal compression fracture † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Brain contusion † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Facial bones fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Foot fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Humerus fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Jaw fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Post procedural complication † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Sternal fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Subcutaneous haematoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Thoracic vertebral fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Tibia fracture † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Accidental overdose † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Coronary vascular graft stenosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Hand fracture † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Radius fracture † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Road traffic accident † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Subdural haematoma † 1	1/1105 (0.09%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Upper limb fracture † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Wrist fracture † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Aspartate aminotransferase increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Blood potassium decreased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
C-reactive protein increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	2	0/18 (0.00%)	0
Heart rate irregular † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hepatic enzyme increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Liver function test increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pancreatic enzymes increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
White blood cell count increased † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	2	0/18 (0.00%)	0
Gamma-glutamyltransferase increased † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Metabolism and nutrition disorders
Hyperkalaemia † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Dehydration † 1	2/1105 (0.18%)	2	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hyperglycaemia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hyponatraemia † 1	2/1105 (0.18%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Acidosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Diabetes mellitus † 1	1/1105 (0.09%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Diabetes mellitus inadequate control † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Hypokalaemia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Type 2 diabetes mellitus † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Musculoskeletal and connective tissue disorders
Muscular weakness † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Osteoarthritis † 1	6/1105 (0.54%)	6	1/1099 (0.09%)	1	0/18 (0.00%)	0
Back pain † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	2	0/18 (0.00%)	0
Intervertebral disc protrusion † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Muscle twitching † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	2	0/18 (0.00%)	0
Haemarthrosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Intervertebral disc degeneration † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Lumbar spinal stenosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Neck pain † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Spinal stenosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Breast cancer † 1	3/1105 (0.27%)	3	1/1099 (0.09%)	1	0/18 (0.00%)	0
Benign gastric neoplasm † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Bladder adenocarcinoma stage unspecified † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Endometrial cancer † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Gastric adenoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lung neoplasm malignant † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Lymphoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Metastatic malignant melanoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Rectal adenocarcinoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Salivary gland cancer † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Prostate cancer † 1	2/1105 (0.18%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Lung neoplasm † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Malignant melanoma † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Mucinous adenocarcinoma of appendix † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Pancreatic carcinoma † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Squamous cell carcinoma of pharynx † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Vulval neoplasm † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Waldenstrom's macroglobulinaemia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Nervous system disorders
Syncope † 1	1/1105 (0.09%)	1	4/1099 (0.36%)	5	0/18 (0.00%)	0
Cerebrovascular accident † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Loss of consciousness † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Seizure † 1	1/1105 (0.09%)	1	2/1099 (0.18%)	2	0/18 (0.00%)	0
Encephalopathy † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Normal pressure hydrocephalus † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Presyncope † 1	2/1105 (0.18%)	2	1/1099 (0.09%)	1	0/18 (0.00%)	0
Dizziness † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Unresponsive to stimuli † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Altered state of consciousness † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Brain injury † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cerebral ventricle dilatation † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Facial paralysis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Generalised tonic-clonic seizure † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Myoclonus † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Paraesthesia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Parkinsonism † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Petit mal epilepsy † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Subarachnoid haemorrhage † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cerebral infarction † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Cerebral ischaemia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Dementia Alzheimer's type † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Epilepsy † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Haemorrhagic stroke † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Hypoaesthesia † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Ischaemic stroke † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Lacunar stroke † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Lumbar radiculopathy † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Partial seizures † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Transient ischaemic attack † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Psychiatric disorders
Depression † 1	2/1105 (0.18%)	2	2/1099 (0.18%)	2	0/18 (0.00%)	0
Aggression † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Delirium † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Delusion † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Agitation † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Completed suicide † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Confusional state † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Disorientation † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Psychotic behaviour † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hallucination, visual † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Psychotic disorder † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Suicidal ideation † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Ureterolithiasis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Chronic kidney disease † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Nephrolithiasis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Urethral meatus stenosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Reproductive system and breast disorders
Prostatitis † 1	0/1105 (0.00%)	0	2/1099 (0.18%)	2	0/18 (0.00%)	0
Benign prostatic hyperplasia † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Cervical polyp † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Cystocele † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	2/1105 (0.18%)	2	2/1099 (0.18%)	3	0/18 (0.00%)	0
Pneumonia aspiration † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pulmonary embolism † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Acute respiratory failure † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Dyspnoea exertional † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pneumothorax † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Pulmonary hypertension † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Respiratory disorder † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Asthma † 1	1/1105 (0.09%)	2	0/1099 (0.00%)	0	0/18 (0.00%)	0
Epistaxis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Lung disorder † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Nasal polyps † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Pneumothorax spontaneous † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Skin and subcutaneous tissue disorders
Angioedema † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Drug eruption † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Drug reaction with eosinophilia and systemic symptoms † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hypersensitivity vasculitis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Rash † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Toxic skin eruption † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Urticaria † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Actinic keratosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Vascular disorders
Hypotension † 1	1/1105 (0.09%)	1	1/1099 (0.09%)	1	0/18 (0.00%)	0
Aortic aneurysm † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Deep vein thrombosis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Haematoma † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Hypertensive urgency † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Orthostatic hypotension † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Peripheral artery stenosis † 1	0/1105 (0.00%)	0	1/1099 (0.09%)	1	0/18 (0.00%)	0
Blood pressure inadequately controlled † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
Thrombosis † 1	1/1105 (0.09%)	1	0/1099 (0.00%)	0	0/18 (0.00%)	0
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Core Phase: Placebo		Core Phase: Elenbecestat 50 mg		Extension Phase: Elenbecestat 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	292/1105 (26.43%)		391/1099 (35.58%)		6/18 (33.33%)
Blood and lymphatic system disorders
Lymphopenia † 1	18/1105 (1.63%)	18	70/1099 (6.37%)	89	0/18 (0.00%)	0
General disorders
Gait disturbance † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Infections and infestations
Nasopharyngitis † 1	67/1105 (6.06%)	80	71/1099 (6.46%)	86	0/18 (0.00%)	0
Upper respiratory tract infection † 1	50/1105 (4.52%)	56	58/1099 (5.28%)	63	0/18 (0.00%)	0
Viral infection † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Injury, poisoning and procedural complications
Accidental overdose † 1	55/1105 (4.98%)	79	66/1099 (6.01%)	101	0/18 (0.00%)	0
Fall † 1	60/1105 (5.43%)	71	61/1099 (5.55%)	79	0/18 (0.00%)	0
Investigations
Blood sodium decreased † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Metabolism and nutrition disorders
Hyponatraemia † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Osteoarthritis † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Pain in extremity † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Nervous system disorders
Dizziness † 1	45/1105 (4.07%)	49	57/1099 (5.19%)	61	0/18 (0.00%)	0
Cognitive disorder † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	2/18 (11.11%)	2
Cerebral microhaemorrhage † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Somnolence † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Psychiatric disorders
Abnormal dreams † 1	36/1105 (3.26%)	42	57/1099 (5.19%)	66	0/18 (0.00%)	0
Nightmare † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Renal and urinary disorders
Urine flow decreased † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Skin and subcutaneous tissue disorders
Rash † 1	22/1105 (1.99%)	26	60/1099 (5.46%)	78	0/18 (0.00%)	0
Alopecia † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
Vascular disorders
Varicose vein † 1	0/1105 (0.00%)	0	0/1099 (0.00%)	0	1/18 (5.56%)	1
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

This study was terminated early due to an unfavorable risk-benefit ratio including no evidence of potential efficacy and the adverse event profile in participants with drug treatment was worse than that in participants who received placebo. The small sample size at the 24 month time point of the core phase limits the interpretability of the data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Eisai Medical Information
• Organization: Eisai Ltd.
• Phone: +1-888-274-2378
• EMail: esi_medinfo@eisai.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bullich S, Mueller A, De Santi S, Koglin N, Krause S, Kaplow J, Kanekiyo M, Roe-Vellve N, Perrotin A, Jovalekic A, Scott D, Gee M, Stephens A, Irizarry M. Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study. Alzheimers Res Ther. 2022 Jul 27;14(1):105. doi: 10.1186/s13195-022-01048-x.

• Responsible Party: Eisai Inc. ( Eisai Co., Ltd. )
• ClinicalTrials.gov Identifier: NCT02956486
• Obsolete Identifiers: NCT03036280
• Other Study ID Numbers: E2609-G000-301; 2016-003928-23 ( EudraCT Number ); 2016-004128-42 ( EudraCT Number )
• First Submitted: November 3, 2016
• First Posted: November 6, 2016
• Results First Submitted: January 14, 2021
• Results First Posted: February 3, 2021
• Last Update Posted: February 3, 2021