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EPOCH: An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Terminated
CT.gov ID
NCT01739348
Collaborator
(none)
2,211
Enrollment
4
Arms
52.4
Actual Duration (Months)

Study Details

Study Description

Brief Summary

This study consists of two parts, Part I and Part II. The purpose of Part I of the study is to assess the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks in the treatment of Alzheimer's Disease (AD). The primary study hypotheses for Part I are that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) score. The first approximately 400 participants entering Part I of the study are identified as the Safety Cohort. Participants who complete Part I of the study may choose to participate in Part II, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks.

Condition or Disease Intervention/Treatment Phase
  • Drug: Verubecestat (Part I and Part II)
  • Drug: Verubecestat (Part I and Part II)
  • Drug: Verubecestat (Part I and Part II)
  • Drug: Placebo (Part I)
  • Drug: Verubecestat (Part II)
 Phase 2/Phase 3

Detailed Description

Two substudies are included in Part I of the study: 1) a medical imaging substudy to evaluate changes in brain amyloid protein load using positron emission tomography (PET) and an amyloid tracer ([18F]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy to evaluate changes in CSF concentrations of amyloid-β related peptides, total tau, and phosphorylated tau (p-tau). The substudies will be conducted only at designated investigational sites. Participants are not required to take part in a substudy in order to take part in the larger trial.

Study Design

Study Type:
Interventional
Actual Enrollment :
2211 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)
Actual Study Start Date :
Nov 30, 2012
Actual Primary Completion Date :
Apr 14, 2017
Actual Study Completion Date :
Apr 14, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

[Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

Drug: Verubecestat (Part I and Part II)
Single 12 mg verubecestat tablet once daily, taken orally
Other Names:
  • SCH 900931

    		•
    Experimental: Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

    [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Drug: Verubecestat (Part I and Part II)
    Single 40 mg verubecestat tablet once daily, taken orally
    Other Names:
  • SCH 900931

    		•
    Experimental: Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

    [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Drug: Verubecestat (Part I and Part II)
    Single 60 or 40 mg verubecestat tablet once daily, taken orally
    Other Names:
  • SCH 900931

    		•
    Placebo Comparator: Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

    [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Drug: Placebo (Part I)
    Single placebo tablet matching verubecestat treatment once daily, taken orally

    Drug: Verubecestat (Part II)
    Single 40 mg verubecestat tablet once daily, taken orally
    Other Names:
  • SCH 900931

    		•

    Outcome Measures

    Primary Outcome Measures

    1. [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score [Baseline and week 78]

      Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score.

    2. [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score [Baseline and week 78]

      Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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.

    3. [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score [Baseline and week 104]

      Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.

    4. [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score [Baseline and week 104]

      Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.

    5. [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event [Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)]

      The number of participants experiencing an adverse event (AE) in Part I 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 II (Extension Study)] Number of Participants Who Experienced an Adverse Event [From week 78 (end of treatment in Part I) up to week 262 of Part II]

      The number of participants experiencing an adverse event (AE) in Part II 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.

    7. [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event [Up to week 78]

      The number of participants discontinuing from study drug due to an AE in Part I 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.

    8. [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event [From week 78 (end of treatment in Part I) up to week 260 of Part II]

      The number of participants discontinuing from study drug due to an AE in Part II 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 I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score [Baseline and week 78]

      Least squares mean change from baseline at week 78 was assessed for CDR-SB score. The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: 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). Scores from each individual domain are summed to the total CDR-SB score, with total scores ranging from 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 I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV) [Baseline and week 78]

      Least squares mean percent change from baseline at week 78 was calculated for Total Hippocampal Volume (THV) as measured by volumetric magnetic resonance imaging (vMRI). Longitudinal analysis of within-participant THV is computed using a change analysis algorithm using tensor-based morphometry. This technique produces one measure of volume change calculated from the registration of serial vMRI scans at the follow-up time point relative to baseline. Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).

    3. [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau [Baseline and week 78]

      Least squares mean fold change from baseline at week 78 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 I, with testing occurring only at select trial sites. Least squares mean fold change from baseline >1 indicates increased Total Tau concentration in the CSF.

    4. [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR) [Baseline and week 78]

      Least squares mean change from baseline at week 78 was calculated for SUVR, a measure of brain cortical amyloid load. Per protocol, SUVR was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Participants receive the PET tracer [18F]Flutemetamol (IV). After 90 minutes, participants receive 4 PET scans (5 minutes each in duration). Using these PET scan images, specific brain ROIs (frontal, temporal, and parietal lobes; anterior and posterior cingulate and precuneus) are used to calculate regional SUVRs, defined as the relative ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). These regional SUVRs are then averaged to compute a composite cortical SUVR for each participant. Higher composite cortical SUVR values indicate increased amyloid load, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.

    5. [Part I (Base Study)] Percentage of Participants Achieving Responder Status [Week 78]

      The percentage of participants achieving responder status at week 78 was assessed. To determine which participants were considered responders, a linear regression was conducted at the participant level, yielding an estimated 78-week rate of change (i.e., a slope) for each participant with respect to ADAS-Cog and ADCS-ADL. To be declared a responder, a participant must have: 1) ADAS-Cog and ADCS-ADL observations at baseline and 78 weeks of treatment; 2) an ADAS-Cog slope > 4.0 over 78 weeks, and 3) an ADCS-ADL slope > -6.3 over 78 weeks. A participant failing to meet any of these criteria was designated as a non-responder at Week 78.

    6. [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score [Baseline and week 78]

      Least squares mean change from baseline at week 78 was assessed for NPI score. NPI is a clinical assessment of psychiatric status, covering 12 domains: delusion; hallucination; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; sleep/nighttime behaviors; and appetite/eating disorders. Based on an interview of the participant's caregiver, each domain is assessed for symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Domain scores [range: 0 to 12] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score [range: 0 (no symptoms in any domain) to 144]. Higher scores reflect more severe psychiatric impairment, with increases in impairment reflected by increases in NPI score.

    7. [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score [Baseline and week 78]

      Least squares mean change from baseline at week 78 was assessed for MMSE score. The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed over the course of 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance. Further, deterioration in cognitive performance would be reflected by decreases in MMSE score.

    Eligibility Criteria

    Criteria

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

    • Diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD

    • AD is of mild to moderate severity

    • Clear history of cognitive and functional decline over at least one year that is either a) documented in medical records or b) documented by history from an informant who knows the subject well

    • Able to read at a 6th grade level or equivalent, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation

    • If a participant is receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E) and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the participant must be willing to remain on the same dose for the duration of the trial. Participants may need to be on AD treatments in accordance with local requirements

    • Participant must have a reliable and competent trial partner/caregiver who must have a close relationship with the subject

    Inclusion Criteria for Extension Period (Part II):

    • Tolerated study drug and completed the initial 78-week period of the trial (Part I)

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

    Exclusion Criteria:

    • History of stroke

    • Evidence of a neurological disorder other than the disease being studied (i.e., probable AD)

    • History of seizures or epilepsy within the last 5 years before Screening

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

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

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

    • 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

    • History of hepatitis or liver disease that has been active within the six months prior to Screening Visit

    • Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that participation in the trial would pose a significant medical risk to the subject. Controlled co-morbid conditions are not exclusionary if stable within three months of the Screening Visit

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

    • History of malignancy occurring within the five years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma; or malignancy which has been treated with potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy

    • Clinically significant vitamin B12 or folate deficiency in the six months before Screening Visit

    • Use of any investigational drugs within 30 days (or longer depending on drug) before Screening or participation in studies involving repeated cognitive testing within 30 days before Screening. Participation in an observational study, such as those involving annual cognitive assessments and/or neuroimaging, may be allowed if approved by Sponsor

    • History of a hypersensitivity reaction to more than three drugs

    • Has tested positive for human immunodeficiency virus (HIV)

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

    Additional Exclusion Criteria for Safety Cohort:

    • History of an ongoing medical condition that has been poorly controlled within 6 months of the Screening Visit (e.g., hypotension, diabetes, hypertension, cerebrovascular disease, thyroid disease, endocrine disturbance, congestive heart failure, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that a subject's participation in the trial would pose a significant medical risk

    • History of congestive heart failure (moderate or greater severity), myocardial infarction, heart surgery, syncope, bradycardia, or clinically significant hypotension within one year before Screening

    Exclusion Criteria for Extension Period (Part II):

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

    • Has developed a recent or ongoing, uncontrolled, clinically significant medical condition other than AD

    • Has history of or has developed during Part I evidence of long QT syndrome, QTc interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes

    • Has developed a form of dementia that is not AD

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT01739348
    Other Study ID Numbers:
    • P07738
    • MK-8931-017
    • 2011-003151-20
    • 132229
    First Posted:
    Dec 3, 2012
    Last Update Posted:
    Oct 24, 2018
    Last Verified:
    Sep 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Alzheimer Disease

    Study Results

    Participant Flow

    Recruitment Details Part I began by enrolling approximately 50 participants per arm (200 total). Enrollment continued until the first 200 participants reached 13 weeks treatment; total enrollment at that time: ~400. For these ~400 participants (Safety Cohort), an interim analysis (IA) was conducted to assess safety. Following IA, enrollment continued (Main Cohort).
    Pre-assignment Detail 2211 participants were randomized in Part I, with 2210 receiving treatment. As planned per protocol, no participants were randomized to the Verubecestat 60 mg arm (Arm C) in the Main Cohort. Participants completing Part I were eligible to continue to Part II. The trial was terminated early and did not complete as planned.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Period Title: Part I (Base Study)
    STARTED 703 700 103 705
    Treated 702 700 103 705
    COMPLETED 501 497 77 516
    NOT COMPLETED 202 203 26 189
    Period Title: Part I (Base Study)
    STARTED 379 366 61 396
    Treated 379 365 61 394
    COMPLETED 0 0 0 0
    NOT COMPLETED 379 366 61 396

    Baseline Characteristics

    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] Total
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. Total of all reporting groups
    Overall Participants 703 700 103 705 2211
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    71.2
    (7.4)
    71.8
    (7.6)
    72.3
    (7.4)
    72.4
    (7.6)
    71.8
    (7.5)
    Sex: Female, Male (Count of Participants)
    Female
    383
    54.5%
    403
    57.6%
    56
    54.4%
    376
    53.3%
    1218
    55.1%
    Male
    320
    45.5%
    297
    42.4%
    47
    45.6%
    329
    46.7%
    993
    44.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.1%
    3
    0.4%
    0
    0%
    3
    0.4%
    7
    0.3%
    Asian
    118
    16.8%
    125
    17.9%
    11
    10.7%
    115
    16.3%
    369
    16.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    8
    1.1%
    13
    1.9%
    2
    1.9%
    7
    1%
    30
    1.4%
    White
    566
    80.5%
    547
    78.1%
    88
    85.4%
    578
    82%
    1779
    80.5%
    More than one race
    4
    0.6%
    4
    0.6%
    2
    1.9%
    0
    0%
    10
    0.5%
    Unknown or Not Reported
    6
    0.9%
    8
    1.1%
    0
    0%
    2
    0.3%
    16
    0.7%
    Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    21.4
    (7.5)
    21.3
    (7.6)
    20.6
    (6.2)
    21.7
    (7.6)
    21.42
    (7.49)
    Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    63.0
    (9.5)
    62.9
    (9.8)
    63.5
    (10.3)
    62.1
    (10.4)
    62.74
    (9.93)
    Clinical Dementia Rating Sum of Boxes (CDR-SB) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    5.4
    (2.1)
    5.3
    (2.1)
    5.5
    (2.3)
    5.6
    (2.3)
    5.43
    (2.17)
    Total Hippocampal Volume (Microliters) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Microliters]
    5894.1
    (1231.5)
    5823.4
    (1189.9)
    5653.5
    (1148.4)
    5800.7
    (1069.2)
    5829.4
    (1162.6)
    Cerebrospinal Fluid (CSF) Total Tau Concentration (picograms (pg)/mL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [picograms (pg)/mL]
    206.7
    (90.4)
    231.5
    (113.9)
    268.6
    (136.2)
    246.2
    (192.9)
    232.2
    (137.3)
    [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR) (SUVR) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [SUVR]
    0.89
    (0.10)
    0.87
    (0.11)
    0.88
    (0.11)
    0.88
    (0.10)
    Neuropsychiatric Inventory (NPI) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    8.7
    (10.5)
    8.2
    (9.8)
    6.9
    (9.5)
    9.2
    (11.6)
    8.64
    (10.6)
    Mini-Mental State Examination (MMSE) Score (Score on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Score on a Scale]
    20.4
    (3.3)
    20.2
    (3.3)
    20.6
    (3.3)
    20.3
    (3.2)
    20.3
    (3.3)

    Outcome Measures

    1. Primary Outcome
    Title [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
    Description Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score.
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 631 626 0 644
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    7.9
    8.0
    7.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6287
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean
    Estimated Value 0.2
    Confidence Interval (2-Sided) 97.51%
    -0.9 to 1.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4625
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Mean
    Estimated Value 0.4
    Confidence Interval (2-Sided) 97.51%
    -0.8 to 1.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
    Description Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window ADCS-ADL observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 627 622 0 636
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    -8.4
    -8.2
    -8.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4925
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.5
    Confidence Interval (2-Sided) 97.51%
    -1.1 to 2.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3221
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.7
    Confidence Interval (2-Sided) 97.51%
    -0.9 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
    Description Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
    Time Frame Baseline and week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants continuing to Part II, with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (FAS population), having an ADAS-Cog observation at week 104. Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 207 208 0 216
    Mean (Standard Deviation) [Score on a Scale]
    10.1
    (9.9)
    8.5
    (9.5)
    9.6
    (9.5)
    4. Primary Outcome
    Title [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
    Description Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
    Time Frame Baseline and week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants continuing to Part II, with a baseline and ≥1 within-analysis-window ADCS-ADL observation subsequent to ≥1 dose of study drug (FAS population), having an ADCS-ADL observation at week 104. Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 207 209 0 216
    Mean (Standard Deviation) [Score on a Scale]
    -10.7
    (13.7)
    -9.2
    (12.7)
    -9.3
    (12.0)
    5. Primary Outcome
    Title [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event
    Description The number of participants experiencing an adverse event (AE) in Part I 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 80 (up to 2 weeks following cessation of study treatment in Part I)

    Outcome Measure Data

    Analysis Population Description
    Includes all randomized participants in Part I receiving ≥1 dose of trial treatment.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 702 700 103 705
    Count of Participants [Participants]
    630
    89.6%
    646
    92.3%
    90
    87.4%
    579
    82.1%
    6. Primary Outcome
    Title [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event
    Description The number of participants experiencing an adverse event (AE) in Part II 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 78 (end of treatment in Part I) up to week 262 of Part II

    Outcome Measure Data

    Analysis Population Description
    Includes all randomized participants continuing to Part II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect AEs occurring in Part II only.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 379 365 61 394
    Count of Participants [Participants]
    240
    34.1%
    230
    32.9%
    51
    49.5%
    264
    37.4%
    7. Primary Outcome
    Title [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
    Description The number of participants discontinuing from study drug due to an AE in Part I 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 78

    Outcome Measure Data

    Analysis Population Description
    Includes all randomized participants in Part I receiving ≥1 dose of trial treatment.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 702 700 103 705
    Count of Participants [Participants]
    57
    8.1%
    64
    9.1%
    12
    11.7%
    42
    6%
    8. Primary Outcome
    Title [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
    Description The number of participants discontinuing from study drug due to an AE in Part II 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 78 (end of treatment in Part I) up to week 260 of Part II

    Outcome Measure Data

    Analysis Population Description
    Includes all randomized participants continuing to Part II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect treatment discontinuations occurring in Part II only.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 379 365 61 394
    Count of Participants [Participants]
    10
    1.4%
    9
    1.3%
    6
    5.8%
    29
    4.1%
    9. Secondary Outcome
    Title [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
    Description Least squares mean change from baseline at week 78 was assessed for CDR-SB score. The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: 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). Scores from each individual domain are summed to the total CDR-SB score, with total scores ranging from 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 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window CDR-SB observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 611 600 0 623
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    2.1
    2.1
    2.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8426
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.0
    Confidence Interval (2-Sided) 97.51%
    -0.4 to 0.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8264
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.0
    Confidence Interval (2-Sided) 97.51%
    -0.3 to 0.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)
    Description Least squares mean percent change from baseline at week 78 was calculated for Total Hippocampal Volume (THV) as measured by volumetric magnetic resonance imaging (vMRI). Longitudinal analysis of within-participant THV is computed using a change analysis algorithm using tensor-based morphometry. This technique produces one measure of volume change calculated from the registration of serial vMRI scans at the follow-up time point relative to baseline. Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window THV observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 308 281 0 308
    Least Squares Mean (95% Confidence Interval) [Percent Change]
    -5.6
    -5.7
    -5.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value -0.6
    Confidence Interval (2-Sided) 97.51%
    -1.0 to -0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value -0.7
    Confidence Interval (2-Sided) 97.51%
    -1.1 to -0.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau
    Description Least squares mean fold change from baseline at week 78 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 I, with testing occurring only at select trial sites. Least squares mean fold change from baseline >1 indicates increased Total Tau concentration in the CSF.
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window CSF Total Tau observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 32 46 0 33
    Least Squares Mean (95% Confidence Interval) [Fold Change]
    1.02
    1.04
    1.07
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2138
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of Fold Change from Baseline
    Estimated Value 0.95
    Confidence Interval (2-Sided) 95%
    0.87 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4330
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of Fold Change from Baseline
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.90 to 1.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)
    Description Least squares mean change from baseline at week 78 was calculated for SUVR, a measure of brain cortical amyloid load. Per protocol, SUVR was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Participants receive the PET tracer [18F]Flutemetamol (IV). After 90 minutes, participants receive 4 PET scans (5 minutes each in duration). Using these PET scan images, specific brain ROIs (frontal, temporal, and parietal lobes; anterior and posterior cingulate and precuneus) are used to calculate regional SUVRs, defined as the relative ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). These regional SUVRs are then averaged to compute a composite cortical SUVR for each participant. Higher composite cortical SUVR values indicate increased amyloid load, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window SUVR observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat did not receive SUVR testing and were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 20 10 0 14
    Least Squares Mean (95% Confidence Interval) [SUVR]
    -0.02
    -0.04
    0.00
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0066
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value -0.03
    Confidence Interval (2-Sided) 95%
    -0.05 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    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 Means
    Estimated Value -0.04
    Confidence Interval (2-Sided) 95%
    -0.06 to -0.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title [Part I (Base Study)] Percentage of Participants Achieving Responder Status
    Description The percentage of participants achieving responder status at week 78 was assessed. To determine which participants were considered responders, a linear regression was conducted at the participant level, yielding an estimated 78-week rate of change (i.e., a slope) for each participant with respect to ADAS-Cog and ADCS-ADL. To be declared a responder, a participant must have: 1) ADAS-Cog and ADCS-ADL observations at baseline and 78 weeks of treatment; 2) an ADAS-Cog slope > 4.0 over 78 weeks, and 3) an ADCS-ADL slope > -6.3 over 78 weeks. A participant failing to meet any of these criteria was designated as a non-responder at Week 78.
    Time Frame Week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants in Part I receiving ≥1 dose of trial treatment. Per protocol, the first 200 participants enrolled prior to IA (across all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded from analysis.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 652 652 0 653
    Number [Percentage of Participants]
    20.1
    2.9%
    19.6
    2.8%
    19.3
    18.7%
    14. Secondary Outcome
    Title [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score
    Description Least squares mean change from baseline at week 78 was assessed for NPI score. NPI is a clinical assessment of psychiatric status, covering 12 domains: delusion; hallucination; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; sleep/nighttime behaviors; and appetite/eating disorders. Based on an interview of the participant's caregiver, each domain is assessed for symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Domain scores [range: 0 to 12] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score [range: 0 (no symptoms in any domain) to 144]. Higher scores reflect more severe psychiatric impairment, with increases in impairment reflected by increases in NPI score.
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window NPI observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 632 631 0 639
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    3.4
    3.8
    2.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2949
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.7
    Confidence Interval (2-Sided) 95%
    -0.6 to 2.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1372
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 1.1
    Confidence Interval (2-Sided) 95%
    -0.4 to 2.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score
    Description Least squares mean change from baseline at week 78 was assessed for MMSE score. The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed over the course of 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance. Further, deterioration in cognitive performance would be reflected by decreases in MMSE score.
    Time Frame Baseline and week 78

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with a baseline and ≥1 within-analysis-window MMSE observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Measure Participants 610 600 0 628
    Least Squares Mean (95% Confidence Interval) [Score on a Scale]
    -3.9
    -3.6
    -4.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4721
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -0.3 to 0.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II], Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0599
    Comments
    Method Longitudinal ANCOVA
    Comments
    Method of Estimation Estimation Parameter Difference in Least Squares Means
    Estimated Value 0.5
    Confidence Interval (2-Sided) 95%
    0.0 to 1.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame [Part I]: Up to week 80 of Part I (up to 2 weeks following cessation of study treatment in Part I); [Part II]: From week 78 (end of treatment in Part I) up to week 262 of Study Part II
    Adverse Event Reporting Description [Part I] Includes all randomized participants in Study Part I (Base Study) receiving ≥1 dose of trial treatment. [Part II] Includes all randomized participants continuing to Study Part II (Extension Study) receiving ≥1 dose of trial treatment in Part II. For Part II-specific arms, only the AEs occurring during study Part II are reported.
    Arm/Group Title Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Arm/Group Description [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    All Cause Mortality
    Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 9/702 (1.3%) 13/700 (1.9%) 3/103 (2.9%) 6/705 (0.9%) 6/379 (1.6%) 4/365 (1.1%) 4/61 (6.6%) 8/394 (2%)
    Serious Adverse Events
    Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 134/702 (19.1%) 162/700 (23.1%) 24/103 (23.3%) 121/705 (17.2%) 57/379 (15%) 56/365 (15.3%) 22/61 (36.1%) 69/394 (17.5%)
    Blood and lymphatic system disorders
    Anaemia 1/702 (0.1%) 1 0/700 (0%) 0 2/103 (1.9%) 2 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 2/61 (3.3%) 2 0/394 (0%) 0
    Haemorrhagic anaemia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Leukocytosis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Neutropenia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cardiac disorders
    Acute coronary syndrome 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Acute myocardial infarction 0/702 (0%) 0 1/700 (0.1%) 2 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Angina unstable 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Arteriosclerosis coronary artery 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Atrial fibrillation 3/702 (0.4%) 3 2/700 (0.3%) 2 3/103 (2.9%) 3 1/705 (0.1%) 1 1/379 (0.3%) 1 2/365 (0.5%) 2 0/61 (0%) 0 1/394 (0.3%) 1
    Bradycardia 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 0/394 (0%) 0
    Cardiac arrest 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Cardiac failure 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Cardiac failure congestive 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 2/394 (0.5%) 2
    Cardio-respiratory arrest 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Coronary artery disease 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Coronary artery occlusion 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Mitral valve incompetence 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Myocardial infarction 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Myocardial ischaemia 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pericardial effusion 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Pericarditis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Sinus bradycardia 1/702 (0.1%) 1 2/700 (0.3%) 3 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Sinus node dysfunction 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Stress cardiomyopathy 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 0/394 (0%) 0
    Torsade de pointes 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Conduction disorder 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ear and labyrinth disorders
    Deafness 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Meniere's disease 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Vertigo positional 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Endocrine disorders
    Thyroid cyst 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Eye disorders
    Cataract 1/702 (0.1%) 1 1/700 (0.1%) 2 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 2/365 (0.5%) 3 0/61 (0%) 0 0/394 (0%) 0
    Corneal oedema 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Glaucoma 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Keratitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Macular oedema 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Retinal detachment 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Trichiasis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 2/394 (0.5%) 2
    Abdominal pain lower 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Abdominal pain upper 2/702 (0.3%) 2 0/700 (0%) 0 1/103 (1%) 1 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Anal prolapse 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Colitis 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 0/394 (0%) 0
    Diarrhoea 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 3/394 (0.8%) 3
    Diverticulum 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Diverticulum oesophageal 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Dysphagia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Enterocolitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Faecaloma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Gastric ulcer 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Gastric ulcer haemorrhage 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Gastrointestinal haemorrhage 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Gastrooesophageal reflux disease 1/702 (0.1%) 1 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Haematemesis 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Haemorrhoids 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ileus 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Incarcerated umbilical hernia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Inguinal hernia 1/702 (0.1%) 1 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Intestinal obstruction 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Large intestinal stenosis 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Large intestine perforation 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Large intestine polyp 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Melaena 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Nausea 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Oesophageal spasm 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Oesophagitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pancreatitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pancreatitis acute 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Retroperitoneal haematoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Small intestinal obstruction 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Upper gastrointestinal haemorrhage 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Vomiting 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    General disorders
    Adverse drug reaction 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Asthenia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 1/365 (0.3%) 1 1/61 (1.6%) 1 0/394 (0%) 0
    Chest discomfort 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Chest pain 1/702 (0.1%) 1 4/700 (0.6%) 4 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 2/365 (0.5%) 2 0/61 (0%) 0 1/394 (0.3%) 1
    Death 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Drowning 1/702 (0.1%) 1 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Euthanasia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Gait disturbance 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 1/379 (0.3%) 1 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    General physical health deterioration 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Incarcerated hernia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Malaise 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Mass 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Non-cardiac chest pain 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Pyrexia 2/702 (0.3%) 2 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 3/394 (0.8%) 3
    Systemic inflammatory response syndrome 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hepatobiliary disorders
    Bile duct stone 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Biliary colic 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cholangitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cholangitis acute 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Cholecystitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Cholecystitis chronic 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cholelithiasis 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hepatic cyst 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hepatitis acute 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Jaundice 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Immune system disorders
    Anaphylactic reaction 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hypersensitivity 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Infections and infestations
    Anal abscess 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Appendicitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bacteraemia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bronchitis 1/702 (0.1%) 1 1/700 (0.1%) 1 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bronchitis viral 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cellulitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Clostridium difficile colitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cystitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Diverticulitis 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 2/379 (0.5%) 2 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Erysipelas 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Escherichia urinary tract infection 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gallbladder empyema 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gastroenteritis 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Gastroenteritis viral 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gastrointestinal infection 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Haematoma infection 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Helicobacter gastritis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Influenza 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Lower respiratory tract infection 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Meningoencephalitis herpetic 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Neurosyphilis 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Osteomyelitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Otitis media acute 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Periorbital cellulitis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Peritonitis 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pneumonia 5/702 (0.7%) 5 6/700 (0.9%) 6 3/103 (2.9%) 3 5/705 (0.7%) 5 3/379 (0.8%) 3 5/365 (1.4%) 5 3/61 (4.9%) 3 4/394 (1%) 4
    Pyelonephritis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Retroperitoneal infection 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Sepsis 0/702 (0%) 0 1/700 (0.1%) 1 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Streptococcal sepsis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Tuberculous pleurisy 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Upper respiratory tract infection 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Urinary tract infection 1/702 (0.1%) 1 1/700 (0.1%) 1 1/103 (1%) 1 2/705 (0.3%) 2 2/379 (0.5%) 2 1/365 (0.3%) 1 1/61 (1.6%) 1 0/394 (0%) 0
    Urosepsis 3/702 (0.4%) 3 1/700 (0.1%) 1 0/103 (0%) 0 2/705 (0.3%) 2 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Anastomotic leak 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ankle fracture 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 2/394 (0.5%) 2
    Carbon monoxide poisoning 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Cervical vertebral fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Comminuted fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Concussion 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Contusion 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Facial bones fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Fall 3/702 (0.4%) 3 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 2/365 (0.5%) 2 1/61 (1.6%) 1 0/394 (0%) 0
    Femoral neck fracture 1/702 (0.1%) 1 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Femur fracture 1/702 (0.1%) 1 1/700 (0.1%) 1 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 2/394 (0.5%) 2
    Fibula fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Foot fracture 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Fracture displacement 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hand fracture 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Head injury 0/702 (0%) 0 1/700 (0.1%) 1 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hip fracture 0/702 (0%) 0 5/700 (0.7%) 5 1/103 (1%) 1 1/705 (0.1%) 1 2/379 (0.5%) 2 2/365 (0.5%) 2 2/61 (3.3%) 2 1/394 (0.3%) 1
    Humerus fracture 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Joint dislocation 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Laceration 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Lumbar vertebral fracture 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Meniscus injury 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Multiple fractures 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Muscle strain 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prescribed overdose 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Radius fracture 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Rib fracture 1/702 (0.1%) 1 2/700 (0.3%) 2 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Skin abrasion 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Spinal compression fracture 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Spinal fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Subarachnoid haemorrhage 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Subdural haematoma 2/702 (0.3%) 2 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Subdural haemorrhage 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Thermal burn 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Thoracic vertebral fracture 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 2/379 (0.5%) 2 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Tibia fracture 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Toxicity to various agents 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Traumatic fracture 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Traumatic intracranial haemorrhage 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Vaccination complication 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ammonia increased 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Aspartate aminotransferase increased 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Blood glucose decreased 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Blood glucose fluctuation 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Electrocardiogram QT prolonged 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Heart rate irregular 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Hepatic enzyme increased 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lipoprotein (a) increased 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Liver function test increased 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prostatic specific antigen increased 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Dehydration 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 3/365 (0.8%) 4 0/61 (0%) 0 1/394 (0.3%) 1
    Diabetes mellitus 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Failure to thrive 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hypercalcaemia 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hypoglycaemia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hypokalaemia 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hypokalaemic syndrome 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hyponatraemia 0/702 (0%) 0 3/700 (0.4%) 3 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 1/394 (0.3%) 1
    Hypophagia 1/702 (0.1%) 1 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metabolic acidosis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Starvation 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Type 2 diabetes mellitus 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/702 (0.1%) 1 0/700 (0%) 0 1/103 (1%) 1 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Arthropathy 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Back pain 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 2 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Chondrocalcinosis pyrophosphate 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Fracture pain 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gouty arthritis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Haemarthrosis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Intervertebral disc protrusion 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Muscle spasms 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Myalgia 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Neck pain 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Osteoarthritis 1/702 (0.1%) 1 3/700 (0.4%) 3 1/103 (1%) 1 3/705 (0.4%) 3 1/379 (0.3%) 1 0/365 (0%) 0 2/61 (3.3%) 2 2/394 (0.5%) 2
    Spinal column stenosis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Tendonitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Adenocarcinoma pancreas 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Atypical fibroxanthoma 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Basal cell carcinoma 9/702 (1.3%) 11 9/700 (1.3%) 14 1/103 (1%) 1 15/705 (2.1%) 17 2/379 (0.5%) 3 3/365 (0.8%) 3 1/61 (1.6%) 1 2/394 (0.5%) 3
    Bladder cancer 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bladder transitional cell carcinoma stage II 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Borderline mucinous tumour of ovary 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bowen's disease 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 3/705 (0.4%) 4 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Breast cancer 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Breast cancer recurrent 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Cholangiocarcinoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Chronic myeloid leukaemia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Colon adenoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Colon cancer 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Extradural neoplasm 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Gastric cancer 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Glioma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Hepatic cancer 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Intraductal proliferative breast lesion 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Invasive ductal breast carcinoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Kaposi's sarcoma 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Keratoacanthoma 1/702 (0.1%) 1 3/700 (0.4%) 3 0/103 (0%) 0 3/705 (0.4%) 3 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lentigo maligna 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lung adenocarcinoma 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lung cancer metastatic 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lung neoplasm malignant 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Lymphoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Malignant melanoma 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 3/705 (0.4%) 3 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Malignant melanoma in situ 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Malignant neoplasm of renal pelvis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metastases to bone 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metastatic malignant melanoma 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metastatic squamous cell carcinoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Myelofibrosis 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Neuroendocrine tumour 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Oesophageal adenocarcinoma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ovarian cancer 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pancreatic carcinoma 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Plasma cell myeloma 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prostate cancer 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prostate cancer metastatic 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Prostatic adenoma 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Rectal cancer 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Sarcoma uterus 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Skin squamous cell carcinoma metastatic 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Small intestine carcinoma 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Squamous cell carcinoma 5/702 (0.7%) 5 3/700 (0.4%) 4 2/103 (1.9%) 2 3/705 (0.4%) 3 5/379 (1.3%) 5 1/365 (0.3%) 1 2/61 (3.3%) 2 0/394 (0%) 0
    Squamous cell carcinoma of head and neck 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Squamous cell carcinoma of lung 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Squamous cell carcinoma of skin 3/702 (0.4%) 4 2/700 (0.3%) 2 1/103 (1%) 1 4/705 (0.6%) 4 1/379 (0.3%) 1 1/365 (0.3%) 1 1/61 (1.6%) 1 0/394 (0%) 0
    Transitional cell carcinoma 0/702 (0%) 0 1/700 (0.1%) 1 1/103 (1%) 1 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Uterine cancer 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Nervous system disorders
    Amnesia 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ataxia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Carotid artery occlusion 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cerebellar infarction 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cerebral infarction 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 1/379 (0.3%) 1 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Cerebrovascular accident 2/702 (0.3%) 2 6/700 (0.9%) 6 0/103 (0%) 0 4/705 (0.6%) 4 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Cognitive disorder 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Dementia 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Dementia Alzheimer's type 1/702 (0.1%) 1 1/700 (0.1%) 1 1/103 (1%) 1 0/705 (0%) 0 1/379 (0.3%) 1 1/365 (0.3%) 1 0/61 (0%) 0 5/394 (1.3%) 5
    Depressed level of consciousness 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Diplegia 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Dizziness 2/702 (0.3%) 2 2/700 (0.3%) 2 0/103 (0%) 0 3/705 (0.4%) 4 0/379 (0%) 0 2/365 (0.5%) 2 0/61 (0%) 0 0/394 (0%) 0
    Encephalopathy 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Epilepsy 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Facial paralysis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Headache 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Intracranial aneurysm 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ischaemic stroke 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Loss of consciousness 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Lumbosacral radiculopathy 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Memory impairment 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Metabolic encephalopathy 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Paraesthesia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Partial seizures 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Presyncope 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 3/379 (0.8%) 3 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Psychomotor skills impaired 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Radiculopathy 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Sciatica 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Seizure 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 2/365 (0.5%) 2 1/61 (1.6%) 1 3/394 (0.8%) 3
    Somnolence 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Syncope 7/702 (1%) 7 13/700 (1.9%) 15 0/103 (0%) 0 5/705 (0.7%) 5 1/379 (0.3%) 1 3/365 (0.8%) 4 2/61 (3.3%) 2 2/394 (0.5%) 2
    Transient ischaemic attack 3/702 (0.4%) 3 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 1/61 (1.6%) 1 1/394 (0.3%) 1
    Psychiatric disorders
    Abnormal behaviour 1/702 (0.1%) 1 2/700 (0.3%) 2 0/103 (0%) 0 2/705 (0.3%) 2 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Aggression 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 2/705 (0.3%) 2 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 2/394 (0.5%) 2
    Agitation 4/702 (0.6%) 5 4/700 (0.6%) 4 1/103 (1%) 1 0/705 (0%) 0 5/379 (1.3%) 6 0/365 (0%) 0 1/61 (1.6%) 2 2/394 (0.5%) 2
    Anxiety 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Completed suicide 2/702 (0.3%) 2 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Confusional state 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 3/705 (0.4%) 3 2/379 (0.5%) 2 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Delirium 0/702 (0%) 0 4/700 (0.6%) 4 1/103 (1%) 1 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Delusion 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 2/379 (0.5%) 2 1/365 (0.3%) 1 1/61 (1.6%) 1 1/394 (0.3%) 1
    Delusional disorder, persecutory type 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Delusional disorder, unspecified type 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Depression 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Disorientation 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Emotional distress 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hallucination 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 1/61 (1.6%) 1 1/394 (0.3%) 1
    Hallucination, auditory 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hallucination, visual 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Major depression 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Mental status changes 1/702 (0.1%) 1 1/700 (0.1%) 1 1/103 (1%) 1 1/705 (0.1%) 1 3/379 (0.8%) 3 1/365 (0.3%) 1 1/61 (1.6%) 1 0/394 (0%) 0
    Neuropsychiatric symptoms 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 3/394 (0.8%) 3
    Paranoia 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Psychogenic movement disorder 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Psychotic disorder 1/702 (0.1%) 2 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Restlessness 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Sleep disorder 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Suicidal behaviour 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Suicidal ideation 2/702 (0.3%) 2 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 1/61 (1.6%) 1 0/394 (0%) 0
    Suicide attempt 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Renal and urinary disorders
    Acute kidney injury 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bladder spasm 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Calculus bladder 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    End stage renal disease 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Haematuria 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Incontinence 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Nephrolithiasis 2/702 (0.3%) 2 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Renal colic 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Stress urinary incontinence 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Ureterolithiasis 2/702 (0.3%) 2 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Urethral disorder 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Urethral stenosis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Urinary incontinence 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Urinary retention 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 1/394 (0.3%) 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 3/702 (0.4%) 3 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Breast pain 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Cystocele 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prostatitis 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Prostatomegaly 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Rectocele 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Bronchitis chronic 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Bronchospasm 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Chronic obstructive pulmonary disease 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 0/394 (0%) 0
    Noninfective bronchitis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Organising pneumonia 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pharyngeal pouch 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pleural effusion 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pneumonia aspiration 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 1/379 (0.3%) 1 0/365 (0%) 0 1/61 (1.6%) 1 2/394 (0.5%) 2
    Pneumothorax 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Pneumothorax spontaneous 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 2 0/394 (0%) 0
    Pulmonary embolism 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 1/365 (0.3%) 1 0/61 (0%) 0 1/394 (0.3%) 1
    Pulmonary fibrosis 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Respiratory failure 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Sleep apnoea syndrome 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 2 0/394 (0%) 0
    Dermal cyst 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Erythema 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Petechiae 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Rash macular 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Rash maculo-papular 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Urticaria 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Vascular disorders
    Aortic stenosis 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Arteriosclerosis 1/702 (0.1%) 1 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Deep vein thrombosis 0/702 (0%) 0 0/700 (0%) 0 1/103 (1%) 1 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Hypertension 0/702 (0%) 0 1/700 (0.1%) 1 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Hypotension 1/702 (0.1%) 1 1/700 (0.1%) 1 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Hypovolaemic shock 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 1/61 (1.6%) 1 0/394 (0%) 0
    Orthostatic hypotension 0/702 (0%) 0 2/700 (0.3%) 2 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Subclavian vein thrombosis 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 0/705 (0%) 0 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 1/394 (0.3%) 1
    Venous thrombosis limb 0/702 (0%) 0 0/700 (0%) 0 0/103 (0%) 0 1/705 (0.1%) 1 0/379 (0%) 0 0/365 (0%) 0 0/61 (0%) 0 0/394 (0%) 0
    Other (Not Including Serious) Adverse Events
    Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 408/702 (58.1%) 440/700 (62.9%) 66/103 (64.1%) 337/705 (47.8%) 135/379 (35.6%) 102/365 (27.9%) 37/61 (60.7%) 144/394 (36.5%)
    Blood and lymphatic system disorders
    Anaemia 8/702 (1.1%) 8 11/700 (1.6%) 11 1/103 (1%) 1 6/705 (0.9%) 6 5/379 (1.3%) 5 1/365 (0.3%) 1 4/61 (6.6%) 5 5/394 (1.3%) 5
    Gastrointestinal disorders
    Constipation 30/702 (4.3%) 32 27/700 (3.9%) 29 9/103 (8.7%) 9 20/705 (2.8%) 20 13/379 (3.4%) 14 3/365 (0.8%) 3 4/61 (6.6%) 5 10/394 (2.5%) 10
    Diarrhoea 56/702 (8%) 65 60/700 (8.6%) 70 4/103 (3.9%) 9 42/705 (6%) 45 8/379 (2.1%) 9 8/365 (2.2%) 8 4/61 (6.6%) 5 9/394 (2.3%) 10
    Infections and infestations
    Bronchitis 24/702 (3.4%) 28 10/700 (1.4%) 11 6/103 (5.8%) 7 19/705 (2.7%) 19 9/379 (2.4%) 12 5/365 (1.4%) 5 2/61 (3.3%) 2 4/394 (1%) 5
    Urinary tract infection 61/702 (8.7%) 79 71/700 (10.1%) 93 15/103 (14.6%) 18 56/705 (7.9%) 68 20/379 (5.3%) 25 18/365 (4.9%) 21 5/61 (8.2%) 6 28/394 (7.1%) 34
    Viral upper respiratory tract infection 60/702 (8.5%) 81 50/700 (7.1%) 60 5/103 (4.9%) 5 42/705 (6%) 49 21/379 (5.5%) 27 11/365 (3%) 12 2/61 (3.3%) 2 10/394 (2.5%) 11
    Injury, poisoning and procedural complications
    Contusion 25/702 (3.6%) 31 30/700 (4.3%) 33 7/103 (6.8%) 9 21/705 (3%) 27 14/379 (3.7%) 21 8/365 (2.2%) 8 2/61 (3.3%) 2 5/394 (1.3%) 5
    Fall 56/702 (8%) 84 59/700 (8.4%) 75 8/103 (7.8%) 8 39/705 (5.5%) 51 31/379 (8.2%) 37 19/365 (5.2%) 25 7/61 (11.5%) 14 22/394 (5.6%) 27
    Investigations
    Weight decreased 47/702 (6.7%) 48 44/700 (6.3%) 44 7/103 (6.8%) 7 21/705 (3%) 22 10/379 (2.6%) 10 8/365 (2.2%) 8 2/61 (3.3%) 2 13/394 (3.3%) 13
    Metabolism and nutrition disorders
    Decreased appetite 19/702 (2.7%) 20 30/700 (4.3%) 31 6/103 (5.8%) 7 16/705 (2.3%) 16 4/379 (1.1%) 4 0/365 (0%) 0 1/61 (1.6%) 1 10/394 (2.5%) 10
    Musculoskeletal and connective tissue disorders
    Arthralgia 36/702 (5.1%) 41 26/700 (3.7%) 26 4/103 (3.9%) 5 21/705 (3%) 23 8/379 (2.1%) 11 7/365 (1.9%) 8 5/61 (8.2%) 5 3/394 (0.8%) 3
    Back pain 36/702 (5.1%) 39 46/700 (6.6%) 49 6/103 (5.8%) 6 30/705 (4.3%) 34 8/379 (2.1%) 8 7/365 (1.9%) 7 2/61 (3.3%) 3 6/394 (1.5%) 6
    Nervous system disorders
    Dizziness 33/702 (4.7%) 34 56/700 (8%) 70 12/103 (11.7%) 15 32/705 (4.5%) 35 9/379 (2.4%) 9 3/365 (0.8%) 3 1/61 (1.6%) 1 8/394 (2%) 10
    Headache 42/702 (6%) 48 52/700 (7.4%) 59 5/103 (4.9%) 7 41/705 (5.8%) 58 4/379 (1.1%) 6 5/365 (1.4%) 5 2/61 (3.3%) 2 6/394 (1.5%) 9
    Psychiatric disorders
    Abnormal dreams 11/702 (1.6%) 11 15/700 (2.1%) 16 6/103 (5.8%) 6 6/705 (0.9%) 6 1/379 (0.3%) 2 1/365 (0.3%) 1 0/61 (0%) 0 3/394 (0.8%) 3
    Agitation 31/702 (4.4%) 32 16/700 (2.3%) 17 5/103 (4.9%) 7 19/705 (2.7%) 20 8/379 (2.1%) 8 5/365 (1.4%) 5 5/61 (8.2%) 6 10/394 (2.5%) 11
    Anxiety 40/702 (5.7%) 41 47/700 (6.7%) 51 8/103 (7.8%) 10 27/705 (3.8%) 29 6/379 (1.6%) 6 6/365 (1.6%) 6 6/61 (9.8%) 6 8/394 (2%) 8
    Depression 47/702 (6.7%) 52 46/700 (6.6%) 48 9/103 (8.7%) 9 38/705 (5.4%) 38 5/379 (1.3%) 5 6/365 (1.6%) 6 5/61 (8.2%) 5 8/394 (2%) 9
    Insomnia 41/702 (5.8%) 42 33/700 (4.7%) 33 6/103 (5.8%) 6 21/705 (3%) 23 12/379 (3.2%) 12 8/365 (2.2%) 8 2/61 (3.3%) 2 10/394 (2.5%) 10
    Suicidal ideation 39/702 (5.6%) 42 45/700 (6.4%) 55 4/103 (3.9%) 4 24/705 (3.4%) 26 12/379 (3.2%) 14 9/365 (2.5%) 9 2/61 (3.3%) 2 12/394 (3%) 13
    Respiratory, thoracic and mediastinal disorders
    Cough 32/702 (4.6%) 38 26/700 (3.7%) 27 6/103 (5.8%) 6 22/705 (3.1%) 23 7/379 (1.8%) 9 9/365 (2.5%) 10 1/61 (1.6%) 1 13/394 (3.3%) 14
    Skin and subcutaneous tissue disorders
    Rash 33/702 (4.7%) 38 26/700 (3.7%) 31 6/103 (5.8%) 6 25/705 (3.5%) 31 7/379 (1.8%) 7 3/365 (0.8%) 3 1/61 (1.6%) 1 8/394 (2%) 8

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The investigator agrees to provide to the sponsor, 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the trial. The sponsor shall have the right to review and comment with respect to publications, abstracts, slides, and manuscripts and the right to review and comment on the data analysis and presentation.

    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 LLC
    ClinicalTrials.gov Identifier:
    NCT01739348
    Other Study ID Numbers:
    • P07738
    • MK-8931-017
    • 2011-003151-20
    • 132229
    First Posted:
    Dec 3, 2012
    Last Update Posted:
    Oct 24, 2018
    Last Verified:
    Sep 1, 2018