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APECS: Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)

Sponsor
Merck Sharp & Dohme Corp. (Industry)
Overall Status
Terminated
CT.gov ID
NCT01953601
Collaborator
(none)
1,454
Enrollment
3
Arms
53.4
Actual Duration (Months)

Study Details

Study Description

Brief Summary

This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.

Condition or Disease Intervention/Treatment Phase
  • Drug: Verubecestat 12 mg (Parts 1 and 2)
  • Drug: Verubecestat 40 mg (Parts 1 and 2)
  • Other: Placebo (Part 1)
 Phase 3

Detailed Description

As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.

Study Design

Study Type:
Interventional
Actual Enrollment :
1454 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects With Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal AD)
Actual Study Start Date :
Nov 5, 2013
Actual Primary Completion Date :
Apr 17, 2018
Actual Study Completion Date :
Apr 17, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)

[Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

Drug: Verubecestat 12 mg (Parts 1 and 2)
Verubecestat 12 mg oral tablet, given once daily.
Other Names:
  • MK-8931

    		•
    Experimental: Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)

    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Drug: Verubecestat 40 mg (Parts 1 and 2)
    Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2.
    Other Names:
  • MK-8931

    		•
    Placebo Comparator: Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)

    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Drug: Verubecestat 40 mg (Parts 1 and 2)
    Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2.
    Other Names:
  • MK-8931

    • Other: Placebo (Part 1)
    Placebo matching verubecestat, given once daily as an oral tablet.

    Outcome Measures

    Primary Outcome Measures

    1. Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104 [Baseline and Week 104 in Part 1]

      LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.

    2. Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 [Baseline and Week 130 (i.e., Week 26 of Part 2)]

      Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.

    3. Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) [Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)]

      The percentage of participants experiencing an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    4. Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) [Up to Week 104 in Part 1]

      The percentage of participants who discontinued from study drug due to an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    5. Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) [From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)]

      The percentage of participants experiencing an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    6. Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) [From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)]

      The percentage of participants who discontinued from study drug due to an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    Secondary Outcome Measures

    1. Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia [Up to Week 104 in Part 1]

      The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years.

    2. Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment [Week 13 and Week 104 in Part 1]

      LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 [no impairment] to 3 [severe impairment]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression.

    3. Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104 [Baseline and Week 104 in Part 1]

      CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline.

    4. Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104 [Baseline and Week 104 in Part 1]

      Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).

    5. Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104 [Baseline and Week 104 in Part 1]

      [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.

    6. Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104 [Baseline and Week 104 in Part 1]

      Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants' trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score.

    7. Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104 [Baseline and Week 104 in Part 1]

      Mean percent change from baseline at week 104 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part 1, with testing occurring only at select trial sites.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Diagnosis of prodromal AD, including the following:

    2. History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant,

    3. Objective impairment in episodic memory by memory test performed at Screening,

    4. Does not meet criteria for dementia, AND

    5. Positive Screening amyloid imaging PET scan using [18F]flutametamol tracer or positive Screening CSF tau:amyloid-β42 (Aβ42) ratio (Participants with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval)

    6. Able to read at a 6th grade level or equivalent

    7. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening

    8. Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication

    Inclusion Criteria for Extension Period (Part 2):

    1. Tolerated study drug and completed the initial 104-week period of the trial (Part 1)

    2. Participant must have a reliable and competent trial partner who must have a close relationship with the subject

    Exclusion Criteria:

    1. History of stroke

    2. Evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD)

    3. History of seizures or epilepsy within the last 5 years

    4. Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission

    5. Participant is at imminent risk of self-harm or of harm to others

    6. History of alcoholism or drug dependency/abuse within the last 5 years before Screening

    7. Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at the Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be substituted for MRI scan to evaluate eligibility

    8. History of hepatitis or liver disease that has been active within the 6 months prior to Screening

    9. Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening

    10. History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma

    11. Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening

    12. Use of any investigational drugs or participation in clinical trials within the 30 days before Screening

    13. History of a hypersensitivity reaction to more than three drugs

    14. Has human immunodeficiency virus (HIV) by medical history

    15. Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth

    16. History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male participants) or ≥480 milliseconds (for female participants), or torsades de pointes

    17. Close family member (including the trial partner, spouse or children) who is among the personnel of the investigational or sponsor staff directly involved with this trial

    Exclusion Criteria for Extension Period (Part 2):

    1. Participant is at imminent risk of self-harm or of harm to others

    2. Has developed a recent or ongoing, uncontrolled, clinically significant medical or psychiatric condition

    3. Results of safety assessments (e.g., laboratory tests) performed in participant at end of Part 1 that are clinically unacceptable to the Investigator

    4. Has developed a form of dementia that is not AD

    5. Has progressed to dementia due to AD per investigator diagnosis in the initial 104-week study (Part 1).

    Exclusion Criteria for NFT PET Substudy (Part 2):
    1. Had one or two PET scans with MK-6240 in the initial 104-week study.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme Corp.

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme Corp.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme Corp.
    ClinicalTrials.gov Identifier:
    NCT01953601
    Other Study ID Numbers:
    • 8931-019
    • 2012-005542-38
    • 142502
    • MK-8931-019
    First Posted:
    Oct 1, 2013
    Last Update Posted:
    May 17, 2019
    Last Verified:
    May 1, 2019
    Additional relevant MeSH terms:
    Alzheimer Disease
    Cognitive Dysfunction

    Study Results

    Participant Flow

    Recruitment Details N=1454 participants with prodromal Alzheimer's Disease (AD) were randomized, with N=1451 receiving study treatment.
    Pre-assignment Detail This trial was conducted in 2 parts: a Base Study (Part 1), followed by an Extension Study (Part 2). Participants completing Part 1 had the option to continue to Part 2.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Period Title: Part 1 (Base Study)
    STARTED 485 484 485
    Treated 483 484 484
    COMPLETED 234 231 239
    NOT COMPLETED 251 253 246
    Period Title: Part 1 (Base Study)
    STARTED 198 191 204
    Treated 197 191 204
    COMPLETED 0 0 0
    NOT COMPLETED 198 191 204

    Baseline Characteristics

    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) Total
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. Total of all reporting groups
    Overall Participants 485 484 485 1454
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    71.7
    (7.1)
    71.0
    (7.4)
    71.6
    (7.1)
    71.4
    (7.2)
    Sex: Female, Male (Count of Participants)
    Female
    229
    47.2%
    244
    50.4%
    213
    43.9%
    686
    47.2%
    Male
    256
    52.8%
    240
    49.6%
    272
    56.1%
    768
    52.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    28
    5.8%
    29
    6%
    29
    6%
    86
    5.9%
    Not Hispanic or Latino
    441
    90.9%
    439
    90.7%
    441
    90.9%
    1321
    90.9%
    Unknown or Not Reported
    16
    3.3%
    16
    3.3%
    15
    3.1%
    47
    3.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    2
    0.4%
    2
    0.1%
    Asian
    79
    16.3%
    85
    17.6%
    84
    17.3%
    248
    17.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    5
    1%
    3
    0.6%
    6
    1.2%
    14
    1%
    White
    397
    81.9%
    392
    81%
    391
    80.6%
    1180
    81.2%
    More than one race
    2
    0.4%
    1
    0.2%
    0
    0%
    3
    0.2%
    Unknown or Not Reported
    2
    0.4%
    3
    0.6%
    2
    0.4%
    7
    0.5%
    Geographic Region (Count of Participants)
    United States / Canada
    226
    46.6%
    224
    46.3%
    226
    46.6%
    676
    46.5%
    Japan
    57
    11.8%
    60
    12.4%
    59
    12.2%
    176
    12.1%
    Europe / Australia / New Zealand
    163
    33.6%
    163
    33.7%
    161
    33.2%
    487
    33.5%
    Other
    37
    7.6%
    37
    7.6%
    38
    7.8%
    112
    7.7%
    APOE4 Genotype (Count of Participants)
    Negative
    155
    32%
    146
    30.2%
    148
    30.5%
    449
    30.9%
    Positive
    328
    67.6%
    337
    69.6%
    335
    69.1%
    1000
    68.8%
    Missing
    0
    0%
    1
    0.2%
    1
    0.2%
    2
    0.1%
    Baseline Use of Vitamin E (Count of Participants)
    No Use
    351
    72.4%
    372
    76.9%
    355
    73.2%
    1078
    74.1%
    ≤400 IU / day
    123
    25.4%
    100
    20.7%
    120
    24.7%
    343
    23.6%
    >400 IU / day
    9
    1.9%
    12
    2.5%
    9
    1.9%
    30
    2.1%
    Background Alzheimer's Disease (AD) Treatment (Count of Participants)
    Use of AChEI alone
    182
    37.5%
    191
    39.5%
    180
    37.1%
    553
    38%
    Use of memantine alone
    9
    1.9%
    8
    1.7%
    8
    1.6%
    25
    1.7%
    Use of AChEI and memantine
    31
    6.4%
    26
    5.4%
    34
    7%
    91
    6.3%
    No use of AChEI or memantine
    261
    53.8%
    259
    53.5%
    262
    54%
    782
    53.8%
    Mini-Mental State Examination (MMSE) Score (Count of Participants)
    MMSE ≥27
    212
    43.7%
    211
    43.6%
    214
    44.1%
    637
    43.8%
    MMSE ≥24-26
    270
    55.7%
    271
    56%
    270
    55.7%
    811
    55.8%
    Missing
    1
    0.2%
    2
    0.4%
    0
    0%
    3
    0.2%
    Clinical Dementia Rating Sum of Boxes (CDR-SB) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    2.7
    (1.3)
    2.7
    (1.3)
    2.6
    (1.2)
    2.66
    (1.25)
    Composite Cognition Score-3 Domain (CCS-3D) (Z-score) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Z-score]
    0.0
    (1.0)
    0.0
    (1.0)
    -0.1
    (1.0)
    -0.01
    (1.00)
    Total Hippocampal Volume (THV) (µL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [µL]
    6448.4
    (1107.1)
    6468.5
    (1105.8)
    6435.4
    (987.2)
    6450.55
    (1063.87)
    [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR) (Standard Uptake Value Ratio (SUVR)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Standard Uptake Value Ratio (SUVR)]
    0.86
    (0.07)
    0.87
    (0.07)
    0.85
    (0.06)
    0.86
    (0.07)
    AD Cooperative Study-Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    42.2
    (5.9)
    43.1
    (5.4)
    42.8
    (5.9)
    42.71
    (5.73)
    Cerebrospinal Fluid (CSF) Total Tau Concentration (pg/mL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [pg/mL]
    203.8
    (129.1)
    159.3
    (79.0)
    243.5
    (97.0)
    202.12
    (101.91)

    Outcome Measures

    1. Primary Outcome
    Title Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104
    Description LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 465 458 469
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    1.6
    2.0
    1.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6734
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value 0.1
    Confidence Interval (2-Sided) 97.51%
    -0.3 to 0.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0141
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means (LSM)
    Estimated Value 0.4
    Confidence Interval (2-Sided) 97.51%
    0.0 to 0.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    2. Primary Outcome
    Title Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130
    Description Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.
    Time Frame Baseline and Week 130 (i.e., Week 26 of Part 2)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants continuing to Part 2, with: 1) both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; 2) a positive test for cortical amyloid load by PET; and 3) a CDR-SB observation at week 130.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 120 113 124
    Mean (Standard Deviation) [Score on a Scale]
    2.0
    (2.5)
    1.9
    (2.2)
    1.5
    (2.1)
    3. Primary Outcome
    Title Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
    Description The percentage of participants experiencing an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
    Time Frame Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants in Part 1, receiving ≥1 dose of study treatment.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 483 484 484
    Number [Percentage of Participants]
    91.3
    18.8%
    92.1
    19%
    87.0
    17.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value 4.32
    Confidence Interval (2-Sided) 95%
    0.40 to 8.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm A - Arm C
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value 5.17
    Confidence Interval (2-Sided) 95%
    1.33 to 9.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm B - Arm C
    4. Primary Outcome
    Title Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
    Description The percentage of participants who discontinued from study drug due to an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
    Time Frame Up to Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    All randomized participants in Part 1, receiving ≥1 dose of study treatment.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 483 484 484
    Number [Percentage of Participants]
    6.6
    1.4%
    10.1
    2.1%
    4.5
    0.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value 2.08
    Confidence Interval (2-Sided) 95%
    -0.84 to 5.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm A - Arm C
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value 5.58
    Confidence Interval (2-Sided) 95%
    2.35 to 8.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm B - Arm C
    5. Primary Outcome
    Title Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
    Description The percentage of participants experiencing an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
    Time Frame From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect AEs occurring in Part 2 only.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 197 191 204
    Number [Percentage of Participants]
    59.4
    12.2%
    55.5
    11.5%
    66.2
    13.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value -6.79
    Confidence Interval (2-Sided) 95%
    -16.16 to 2.68
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm A - Arm C
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value -10.68
    Confidence Interval (2-Sided) 95%
    -20.16 to -1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm B - Arm C
    6. Primary Outcome
    Title Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
    Description The percentage of participants who discontinued from study drug due to an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
    Time Frame From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect discontinuations occurring in Part 2 only.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 197 191 204
    Number [Percentage of Participants]
    1.0
    0.2%
    1.0
    0.2%
    3.4
    0.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value -2.42
    Confidence Interval (2-Sided) 95%
    -6.03 to 0.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm A - Arm C
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in % vs Placebo
    Estimated Value -2.38
    Confidence Interval (2-Sided) 95%
    -6.01 to 0.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in % = Arm B - Arm C
    7. Secondary Outcome
    Title Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia
    Description The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years.
    Time Frame Up to Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment in Part 1 who tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 480 481 481
    Number [Event-Rate / 100 Participant-Years]
    24.5
    25.5
    19.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0222
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.301
    Confidence Interval (2-Sided) 97.51%
    1.005 to 1.684
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR = Arm A / Arm C
    Other Statistical Analysis Based on Cox regression model with Efron's method of tie handling with treatment, background AD treatment (use, no use), sex, APOE4 status (carrier, non-carrier) and baseline use of Vitamin E as categorical covariates and age and baseline MMSE value as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0050
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.382
    Confidence Interval (2-Sided) 97.51%
    1.067 to 1.790
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR = Arm B / Arm C
    Other Statistical Analysis Based on Cox regression model with Efron's method of tie handling with treatment, background AD treatment (use, no use), sex, APOE4 status (carrier, non-carrier) and baseline use of Vitamin E as categorical covariates and age and baseline MMSE value as continuous covariates.
    8. Secondary Outcome
    Title Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment
    Description LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 [no impairment] to 3 [severe impairment]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression.
    Time Frame Week 13 and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 465 458 469
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    1.5
    1.8
    1.5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9109
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 97.51%
    -0.3 to 0.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0824
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value 0.3
    Confidence Interval (2-Sided) 97.51%
    -0.1 to 0.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    9. Secondary Outcome
    Title Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104
    Description CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline.
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CCS-3D observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 441 424 440
    Least Squares Mean (95% Confidence Interval) [Z-score]
    0.8
    0.8
    0.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9510
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 97.51%
    -0.2 to 0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9392
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 97.51%
    -0.2 to 0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    10. Secondary Outcome
    Title Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104
    Description Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose THV observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 168 181 191
    Least Squares Mean (95% Confidence Interval) [Percent Change]
    -6.5
    -6.7
    -6.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1133
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -0.4
    Confidence Interval (2-Sided) 97.51%
    -1.0 to 0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0310
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -0.6
    Confidence Interval (2-Sided) 97.51%
    -1.2 to 0.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    11. Secondary Outcome
    Title Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104
    Description [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose SUVR observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 63 59 65
    Least Squares Mean (95% Confidence Interval) [Standard Uptake Value Ratio (SUVR)]
    -0.03
    -0.04
    0.02
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -0.05
    Confidence Interval (2-Sided) 97.51%
    -0.06 to -0.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -0.06
    Confidence Interval (2-Sided) 97.51%
    -0.07 to -0.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    12. Secondary Outcome
    Title Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104
    Description Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants' trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score.
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose ADCS-ADL MCI observation; and 2) tested positive for cortical amyloid load by PET.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 469 462 472
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    -5.2
    -5.8
    -4.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0960
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -1.0
    Confidence Interval (2-Sided) 97.51%
    -2.4 to 0.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm A - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2), Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0110
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean (LSM)
    Estimated Value -1.7
    Confidence Interval (2-Sided) 97.51%
    -3.2 to -0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in LSM = Arm B - Arm C
    Other Statistical Analysis Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    13. Secondary Outcome
    Title Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104
    Description Mean percent change from baseline at week 104 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part 1, with testing occurring only at select trial sites.
    Time Frame Baseline and Week 104 in Part 1

    Outcome Measure Data

    Analysis Population Description
    Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose observation for CSF Total Tau concentration; and 2) tested positive for cortical amyloid load by PET. CSF Total Tau concentration was analyzed at select trial sites as a Part 1 substudy.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 5 6 6
    Mean (Standard Deviation) [Percent Change]
    33.2
    (44.3)
    42.8
    (39.7)
    10.2
    (27.9)

    Adverse Events

    Time Frame [Part 1]: Up to Week 106 of Part 1 (up to 2 weeks following cessation of study treatment in Part 1); [Part 2]: From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2).
    Adverse Event Reporting Description [Part 1] Includes all randomized participants in Part 1 (Base Study) receiving ≥1 dose of study treatment. [Part 2] Includes all randomized participants continuing to Part 2 (Extension Study) receiving ≥1 dose of study treatment in Part 2. For Part 2-specific arms, only the AEs occurring during Part 2 are reported.
    Arm/Group Title Arm A. Verubecestat 12 mg (Part 1) Arm B. Verubecestat 40 mg (Part 1) Arm C. Placebo (Part 1) Arm A. Verubecestat 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 2) Arm C. Verubecestat 40 mg (Part 2)
    Arm/Group Description [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    All Cause Mortality
    Arm A. Verubecestat 12 mg (Part 1) Arm B. Verubecestat 40 mg (Part 1) Arm C. Placebo (Part 1) Arm A. Verubecestat 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 2) Arm C. Verubecestat 40 mg (Part 2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/483 (0.6%) 1/484 (0.2%) 3/484 (0.6%) 0/197 (0%) 3/191 (1.6%) 0/204 (0%)
    Serious Adverse Events
    Arm A. Verubecestat 12 mg (Part 1) Arm B. Verubecestat 40 mg (Part 1) Arm C. Placebo (Part 1) Arm A. Verubecestat 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 2) Arm C. Verubecestat 40 mg (Part 2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 124/483 (25.7%) 101/484 (20.9%) 96/484 (19.8%) 10/197 (5.1%) 22/191 (11.5%) 24/204 (11.8%)
    Blood and lymphatic system disorders
    Pancytopenia 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Cardiac disorders
    Acute myocardial infarction 1/483 (0.2%) 1 1/484 (0.2%) 1 2/484 (0.4%) 2 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Angina pectoris aggravated 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Angina unstable 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Aortic valve stenosis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Arrhythmia 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Atrial fibrillation 1/483 (0.2%) 1 0/484 (0%) 0 2/484 (0.4%) 3 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Atrial fibrillation aggravated 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Atrial fibrillation with rapid ventricular response 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Atrial flutter 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bradycardia 1/483 (0.2%) 1 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Cardiac failure congestive 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Coronary artery disease 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Coronary artery disease aggravated 2/483 (0.4%) 2 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Myocardial infarction 0/483 (0%) 0 2/484 (0.4%) 2 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Non ST segment elevation myocardial infarction 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Paroxysmal supraventricular tachycardia 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Recurrent atrial fibrillation 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Sick sinus syndrome 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Sinus bradycardia 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Supraventricular tachycardia 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Ventricular bigeminy 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cardio-respiratory arrest 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Right coronary artery stenosis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Congenital, familial and genetic disorders
    Bronchogenic cyst 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Ear and labyrinth disorders
    Benign paroxysmal positional vertigo 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Vertigo 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Eye disorders
    Cataract 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cataract bilateral NOS 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Right cataract 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Acute enterocolitis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Colitis 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Colitis ischaemic 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Diarrhoea 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Diverticular perforation 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Duodenal ulcer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastric ulcer 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastritis 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastrointestinal obstruction 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastrointestinal upset 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastrooesophageal reflux disease 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Haematochezia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Haemorrhoids aggravated 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Indirect inguinal hernia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Intestinal obstruction 2/483 (0.4%) 2 0/484 (0%) 0 1/484 (0.2%) 3 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Large intestine polyp 2/483 (0.4%) 2 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Left inguinal hernia 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Left upper quadrant pain 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Oesophageal ulcer 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rectal prolapse 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 2 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Reflux oesophagitis 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Right inguinal hernia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Small intestinal obstruction 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Tenderness epigastric 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Upper gastrointestinal haemorrhage 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Vomiting 0/483 (0%) 0 2/484 (0.4%) 2 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Diverticular disease 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Duodenal ulcer perforation 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Pancreatitis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Pyloric ulcer perforation 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    General disorders
    Acute chest pain 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Chest pain 3/483 (0.6%) 3 2/484 (0.4%) 3 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Chest pain aggravated 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Chest pressure 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Fever 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Fever of unknown origin 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gait abnormal 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Non-cardiac chest pain 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hepatobiliary disorders
    Bile duct stone 2/483 (0.4%) 2 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Biliary tract disorder 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cholangitis 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cholecystitis 0/483 (0%) 0 0/484 (0%) 0 2/484 (0.4%) 2 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cholelithiasis 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Immune system disorders
    Hypersensitivity reaction 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Infections and infestations
    Acute appendicitis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Acute diverticulitis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bacillus bacteraemia 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bacterial parotitis 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bacterial sepsis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cellulitis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cellulitis of foot 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cellulitis of hand 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cellulitis of leg 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Diverticulitis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Influenza B virus infection 0/483 (0%) 0 2/484 (0.4%) 2 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Liver abscess 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lobar pneumonia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lung infection 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Osteomyelitis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Osteomyelitis acute 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pneumonia 2/483 (0.4%) 2 2/484 (0.4%) 2 3/484 (0.6%) 4 1/197 (0.5%) 1 0/191 (0%) 0 0/204 (0%) 0
    Pneumonia bacterial 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 2 0/204 (0%) 0
    Postoperative wound infection 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Prosthesis related infection 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pseudomonas infection 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pyelonephritis 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Septic arthritis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Septic shock 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Spinal cord infection 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Urinary tract infection 3/483 (0.6%) 3 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Viral infection 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Viral syndrome 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bacterial prostatitis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 1/197 (0.5%) 1 0/191 (0%) 0 0/204 (0%) 0
    Gastroenteritis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Influenza A virus infection 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Nasopharyngitis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Injury, poisoning and procedural complications
    Alcohol intoxication 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Arm fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bimalleolar fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bruise of head 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cervical vertebral fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Chronic subdural haematoma 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Clavicle fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Fall 1/483 (0.2%) 1 1/484 (0.2%) 2 3/484 (0.6%) 3 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Femoral neck fracture 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Femur fracture 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Finger injury 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Fracture of intertrochanteric section of femur, closed 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Fractured mandible 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Head injury 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hip fracture 2/483 (0.4%) 2 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Humerus fracture 1/483 (0.2%) 1 2/484 (0.4%) 2 2/484 (0.4%) 2 0/197 (0%) 0 1/191 (0.5%) 1 1/204 (0.5%) 1
    Joint ligament rupture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lumbar spine compression fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lumbar vertebral fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Multiple fractures 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Near drowning 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Olecranon fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pain trauma activated 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Patella fracture 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pelvic fracture 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Post procedural pain 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Postoperative haematoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Postoperative hypotension 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Radius fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rib fracture 2/483 (0.4%) 2 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Scapula fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Spinal compression fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Subarachnoid bleeding 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Subarachnoid haemorrhage 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Subdural haematoma (traumatic) 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Thoracic vertebral fracture 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Thoracic vertebral fracture T12 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Traffic accident 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Trochanteric femoral fracture 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Vertebral fracture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Wound dehiscence 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Concussion 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Traumatic fracture 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Wrist fracture 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Investigations
    Creatinine increased 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Faecal occult blood 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Prostatic specific antigen increased 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Troponin increased 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 2/483 (0.4%) 2 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hypokalaemia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hyponatraemia 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hyponatraemia aggravated 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hypercalcaemia 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cervical spinal stenosis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cervical spondylosis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Costochondritis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Coxarthrosis 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Herniated disc 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Herniated nucleus pulposus 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hips osteoarthritis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Knee osteoarthritis 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lumbar disc herniation 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Musculoskeletal chest pain 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Myalgia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Osteoarthritis aggravated 3/483 (0.6%) 3 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Osteoporosis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rhabdomyolysis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rotator cuff syndrome 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rotator cuff tear 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Spinal stenosis NOS 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Back muscle spasms 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Adenocarcinoma of prostate 0/483 (0%) 0 2/484 (0.4%) 2 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Atypical fibroxanthoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Basal cell carcinoma 13/483 (2.7%) 14 8/484 (1.7%) 10 6/484 (1.2%) 7 4/197 (2%) 4 2/191 (1%) 2 3/204 (1.5%) 3
    Bladder cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bladder neoplasm 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Bowen's disease 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Breast cancer 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Breast cancer metastatic 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Breast cancer recurrent 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Carcinoma in situ of breast ductal 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cervical cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Chronic lymphocytic leukaemia 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Clear cell renal cell carcinoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Colonic tubular adenoma 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Endometrial cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Follicular thyroid cancer 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastric adenoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Gastric cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Lentigo melanoma 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lip basal cell carcinoma 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 2 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lung adenocarcinoma 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lung adenocarcinoma metastatic 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Malignant melanoma 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Malignant melanoma in situ 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Melanoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Melanoma in situ 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Metastases to lymph nodes 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Metastatic gastric cancer 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Multiple myeloma 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Nodular basal cell carcinoma 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pancreas cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Prostate cancer 3/483 (0.6%) 3 2/484 (0.4%) 2 5/484 (1%) 5 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Prostate cancer recurrent 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 1/191 (0.5%) 1 1/204 (0.5%) 1
    Prostate carcinoma 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Rectal cancer 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Renal cancer 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Skin cancer 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Skin carcinoma 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Squamous cell carcinoma 3/483 (0.6%) 3 2/484 (0.4%) 2 2/484 (0.4%) 2 1/197 (0.5%) 1 0/191 (0%) 0 0/204 (0%) 0
    Squamous cell carcinoma of head and neck 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Squamous cell carcinoma of skin 5/483 (1%) 6 3/484 (0.6%) 4 5/484 (1%) 5 1/197 (0.5%) 1 0/191 (0%) 0 0/204 (0%) 0
    Squamous cell carcinoma of skin in situ 1/483 (0.2%) 2 2/484 (0.4%) 2 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 4 1/204 (0.5%) 2
    Squamous cell carcinoma of skin well differentiated 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Squamous cell carcinoma of the nasal cavity 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Superficial basal cell carcinoma 3/483 (0.6%) 3 0/484 (0%) 0 3/484 (0.6%) 3 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Throat cancer 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Transitional cell carcinoma 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Urothelial carcinoma 1/483 (0.2%) 1 0/484 (0%) 0 2/484 (0.4%) 2 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Invasive ductal breast carcinoma 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Nervous system disorders
    Ataxia 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cerebrovascular accident 0/483 (0%) 0 2/484 (0.4%) 2 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cerebrovascular insufficiency 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Complex partial seizures 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Dementia 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Dementia aggravated 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Dizziness 1/483 (0.2%) 1 1/484 (0.2%) 1 1/484 (0.2%) 1 1/197 (0.5%) 1 0/191 (0%) 0 0/204 (0%) 0
    Embolic stroke 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Epileptic seizure 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Felt faint 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Haemorrhagic stroke 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Headache 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Lightheadedness 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Neurocardiogenic syncope 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Nonconvulsive status epilepticus 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Presyncope 0/483 (0%) 0 1/484 (0.2%) 2 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Seizure 2/483 (0.4%) 2 1/484 (0.2%) 1 0/484 (0%) 0 1/197 (0.5%) 1 1/191 (0.5%) 1 0/204 (0%) 0
    Stroke 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Syncopal attack 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Syncope 5/483 (1%) 5 1/484 (0.2%) 1 1/484 (0.2%) 2 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Thalamic infarction 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Transient cerebral ischaemia 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Transient global amnesia 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Transient ischaemic attack 0/483 (0%) 0 3/484 (0.6%) 4 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Tremor aggravated 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Unconsciousness 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Dysarthria 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Lacunar infarction 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Neurologic reaction 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Psychiatric disorders
    Abnormal behaviour 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Acute mania 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Agitation 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Anxiety 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Confusion aggravated 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Delirium 3/483 (0.6%) 3 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Delusion 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Disorientation 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Major depression 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Mental status changes 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Panic attack 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Psychosis aggravated 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Psychotic disorder 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Psychotic episode 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Somatisation disorder 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Suicidal ideation 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Suicide attempt 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Unsuccessful suicide 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Acute delirium 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Calculus renal 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Calculus ureteric 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Haematuria 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hydronephrosis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Kidney stone 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Renal failure acute 1/483 (0.2%) 1 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Renal mass 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Stone urinary bladder 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Stress urinary incontinence 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Ureteral stricture 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Ureterolithiasis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Urolithiasis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Reproductive system and breast disorders
    Bartholin's cyst 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Benign prostatic hypertrophy 1/483 (0.2%) 1 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Cystocele 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Urogenital prolapse 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Ovarian cyst 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease exacerbation 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Collapse of lung 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Dyspnoea 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Epistaxis 0/483 (0%) 0 1/484 (0.2%) 1 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Haemoptysis 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pharyngeal haematoma 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pleural effusion 0/483 (0%) 0 2/484 (0.4%) 2 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pulmonary embolism 2/483 (0.4%) 2 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Pulmonary oedema 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Haemothorax 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Pneumothorax 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Respiratory distress 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Skin and subcutaneous tissue disorders
    Exanthem 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Urticarial rash 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hives 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 1/204 (0.5%) 1
    Vascular disorders
    Aortic aneurysm 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Arterial stenosis 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Deep vein thrombosis 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Hypertensive episode 0/483 (0%) 0 0/484 (0%) 0 1/484 (0.2%) 1 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Intermittent claudication 0/483 (0%) 0 1/484 (0.2%) 1 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Peripheral obliterative arteriopathy 1/483 (0.2%) 1 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Aortic stenosis 0/483 (0%) 0 0/484 (0%) 0 0/484 (0%) 0 0/197 (0%) 0 1/191 (0.5%) 1 0/204 (0%) 0
    Other (Not Including Serious) Adverse Events
    Arm A. Verubecestat 12 mg (Part 1) Arm B. Verubecestat 40 mg (Part 1) Arm C. Placebo (Part 1) Arm A. Verubecestat 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 2) Arm C. Verubecestat 40 mg (Part 2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 221/483 (45.8%) 223/484 (46.1%) 202/484 (41.7%) 39/197 (19.8%) 31/191 (16.2%) 40/204 (19.6%)
    Gastrointestinal disorders
    Diarrhoea 28/483 (5.8%) 35 21/484 (4.3%) 22 36/484 (7.4%) 38 6/197 (3%) 7 2/191 (1%) 2 3/204 (1.5%) 3
    Infections and infestations
    Cold 16/483 (3.3%) 20 25/484 (5.2%) 28 24/484 (5%) 34 1/197 (0.5%) 1 4/191 (2.1%) 4 3/204 (1.5%) 3
    Common cold syndrome 22/483 (4.6%) 33 32/484 (6.6%) 48 26/484 (5.4%) 38 9/197 (4.6%) 10 3/191 (1.6%) 3 3/204 (1.5%) 3
    Upper respiratory tract infection 31/483 (6.4%) 37 21/484 (4.3%) 24 31/484 (6.4%) 38 3/197 (1.5%) 4 6/191 (3.1%) 6 4/204 (2%) 4
    Urinary tract infection 30/483 (6.2%) 37 26/484 (5.4%) 35 23/484 (4.8%) 30 3/197 (1.5%) 3 3/191 (1.6%) 4 8/204 (3.9%) 10
    Injury, poisoning and procedural complications
    Fall 42/483 (8.7%) 56 36/484 (7.4%) 48 33/484 (6.8%) 41 8/197 (4.1%) 8 6/191 (3.1%) 8 7/204 (3.4%) 10
    Investigations
    Weight decreased 27/483 (5.6%) 27 32/484 (6.6%) 32 10/484 (2.1%) 10 6/197 (3%) 6 0/191 (0%) 0 8/204 (3.9%) 8
    Nervous system disorders
    Dizziness 37/483 (7.7%) 49 31/484 (6.4%) 36 25/484 (5.2%) 25 4/197 (2%) 4 6/191 (3.1%) 6 4/204 (2%) 4
    Headache 32/483 (6.6%) 36 26/484 (5.4%) 27 24/484 (5%) 28 0/197 (0%) 0 0/191 (0%) 0 0/204 (0%) 0
    Psychiatric disorders
    Depression 17/483 (3.5%) 17 28/484 (5.8%) 29 13/484 (2.7%) 15 3/197 (1.5%) 3 0/191 (0%) 0 2/204 (1%) 2
    Suicidal ideation 31/483 (6.4%) 48 40/484 (8.3%) 50 25/484 (5.2%) 26 6/197 (3%) 6 5/191 (2.6%) 5 5/204 (2.5%) 5

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme Corp.
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme Corp.
    ClinicalTrials.gov Identifier:
    NCT01953601
    Other Study ID Numbers:
    • 8931-019
    • 2012-005542-38
    • 142502
    • MK-8931-019
    First Posted:
    Oct 1, 2013
    Last Update Posted:
    May 17, 2019
    Last Verified:
    May 1, 2019