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

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ClinicalTrials.gov Identifier: NCT01739348
Recruitment Status : Terminated
First Posted : December 3, 2012
Results First Posted : May 16, 2018
Last Update Posted : October 24, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Alzheimer's Disease
Interventions Drug: Verubecestat (Part I and Part II)
Drug: Placebo (Part I)
Drug: Verubecestat (Part II)
Enrollment 2211
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 Details 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]
Hide 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
Reason Not Completed
Adverse Event             41             52             8             33
Death             10             7             2             8
Lack of Efficacy             3             8             0             7
Lost to Follow-up             4             2             4             4
Non-Compliance with Study Drug             3             2             0             0
Physician Decision             10             7             1             4
Protocol Violation             2             0             1             2
Screen Failure             2             0             0             0
Site Discontinued Study Participation             1             3             0             0
Study Terminated by Sponsor             72             73             0             86
Participant Moved             4             3             1             7
Trial Partner/Caregiver Withdrew Consent             27             25             2             18
Withdrawal by Subject             23             21             7             20
Period Title: Part II (Extension Study)
Started 379 [1] 366 [1] 61 [1] 396 [1]
Treated 379 365 61 394
Completed 0 0 0 0
Not Completed 379 366 61 396
Reason Not Completed
Adverse Event             10             11             7             26
Death             3             3             2             6
Lack of Efficacy             1             5             0             1
Lost to Follow-up             3             4             0             1
Non-Compliance with Study Drug             0             0             0             1
Physician Decision             7             11             6             12
Study Terminated by Sponsor             329             315             34             323
Participant Moved             3             3             0             3
Trial Partner/Caregiver Withdrew Consent             18             12             8             16
Withdrawal by Subject             5             2             4             7
[1]
Number started refers only to participants completing Part I, volunteering to continue to Part II.
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
Hide 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 Number of Baseline Participants 703 700 103 705 2211
Hide Baseline Analysis Population Description
All randomized participants in Study Part I (Base Study)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 703 participants 700 participants 103 participants 705 participants 2211 participants
71.2  (7.4) 71.8  (7.6) 72.3  (7.4) 72.4  (7.6) 71.8  (7.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 703 participants 700 participants 103 participants 705 participants 2211 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)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 703 participants 700 participants 103 participants 705 participants 2211 participants
American Indian or Alaska Native
1
   0.1%
3
   0.4%
0
   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
   0.0%
0
   0.0%
Black or African American
8
   1.1%
13
   1.9%
2
   1.9%
7
   1.0%
30
   1.4%
White
566
  80.5%
547
  78.1%
88
  85.4%
578
  82.0%
1779
  80.5%
More than one race
4
   0.6%
4
   0.6%
2
   1.9%
0
   0.0%
10
   0.5%
Unknown or Not Reported
6
   0.9%
8
   1.1%
0
   0.0%
2
   0.3%
16
   0.7%
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score on a Scale
Number Analyzed 681 participants 672 participants 97 participants 694 participants 2144 participants
21.4  (7.5) 21.3  (7.6) 20.6  (6.2) 21.7  (7.6) 21.42  (7.49)
[1]
Measure Description: 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.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (Full Analysis Set [FAS] population).
Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score on a Scale
Number Analyzed 677 participants 668 participants 98 participants 686 participants 2129 participants
63.0  (9.5) 62.9  (9.8) 63.5  (10.3) 62.1  (10.4) 62.74  (9.93)
[1]
Measure Description: 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.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for ADCS-ADL subsequent to ≥1 dose of study drug (FAS population).
Clinical Dementia Rating Sum of Boxes (CDR-SB) Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score on a Scale
Number Analyzed 660 participants 643 participants 91 participants 673 participants 2067 participants
5.4  (2.1) 5.3  (2.1) 5.5  (2.3) 5.6  (2.3) 5.43  (2.17)
[1]
Measure Description: 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). Individual domain scores sum to the total CDR-SB score, with total scores ranging from 0-18. Higher scores indicate more severe cognitive impairment.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CDR-SB subsequent to ≥1 dose of study drug (FAS population).
Total Hippocampal Volume   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Microliters
Number Analyzed 332 participants 307 participants 55 participants 346 participants 1040 participants
5894.1  (1231.5) 5823.4  (1189.9) 5653.5  (1148.4) 5800.7  (1069.2) 5829.4  (1162.6)
[1]
Measure Description: Total Hippocampal Volume (THV) was measured by volumetric magnetic resonance imaging (vMRI).
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for THV subsequent to ≥1 dose of study drug (FAS population).
Cerebrospinal Fluid (CSF) Total Tau Concentration   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Picograms (pg)/mL
Number Analyzed 38 participants 57 participants 12 participants 41 participants 148 participants
206.7  (90.4) 231.5  (113.9) 268.6  (136.2) 246.2  (192.9) 232.2  (137.3)
[1]
Measure Description: Total Tau concentration in the cerebrospinal fluid (CSF) was monitored as a measure of brain tau pathology.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CSF Total Tau subsequent to ≥1 dose of study drug (FAS population). Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring at select trial sites.
[18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  SUVR
Number Analyzed 20 participants 10 participants 0 participants 14 participants 44 participants
0.89  (0.10) 0.87  (0.11) 0.88  (0.11) 0.88  (0.10)
[1]
Measure Description: [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants receive 4 PET scans. Using the PET scan images, regional SUVRs are calculated for brain regions of interest (ROIs), defined as the ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). Regional SUVRs are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load.
[2]
Measure 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). SUVR testing occurred at select sites as a Part I substudy. Per protocol, SUVR was not analyzed for the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat.
Neuropsychiatric Inventory (NPI) Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score on a Scale
Number Analyzed 682 participants 679 participants 100 participants 691 participants 2152 participants
8.7  (10.5) 8.2  (9.8) 6.9  (9.5) 9.2  (11.6) 8.64  (10.6)
[1]
Measure Description: NPI is a clinical assessment of psychiatric status, covering 12 domains. 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.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1 within-analysis-window NPI observation subsequent to ≥1 dose of study drug (FAS population).
Mini-Mental State Examination (MMSE) Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score on a Scale
Number Analyzed 660 participants 648 participants 98 participants 679 participants 2085 participants
20.4  (3.3) 20.2  (3.3) 20.6  (3.3) 20.3  (3.2) 20.3  (3.3)
[1]
Measure Description: The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed with 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.
[2]
Measure Analysis Population Description: All randomized participants (Part I) with a baseline and ≥1within-analysis-window MMSE observation subsequent to ≥1 dose of study drug (FAS population).
1.Primary Outcome
Title [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 631 626 0 644
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
7.9
(7.2 to 8.6)
8.0
(7.3 to 8.7)
7.7
(7.0 to 8.4)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6287
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4625
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
2.Primary Outcome
Title [Part I (Base Study)] Change From Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 627 622 0 636
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
-8.4
(-9.5 to -7.4)
-8.2
(-9.2 to -7.1)
-8.9
(-9.9 to -8.0)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4925
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3221
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
3.Primary Outcome
Title [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 207 208 0 216
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 207 209 0 216
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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)
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 702 700 103 705
Measure Type: Count of Participants
Unit of Measure: Participants
630
  89.7%
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
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 379 365 61 394
Measure Type: Count of Participants
Unit of Measure: Participants
240
  63.3%
230
  63.0%
51
  83.6%
264
  67.0%
7.Primary Outcome
Title [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 702 700 103 705
Measure Type: Count of Participants
Unit of Measure: Participants
57
   8.1%
64
   9.1%
12
  11.7%
42
   6.0%
8.Primary Outcome
Title [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 379 365 61 394
Measure Type: Count of Participants
Unit of Measure: Participants
10
   2.6%
9
   2.5%
6
   9.8%
29
   7.4%
9.Secondary Outcome
Title [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 611 600 0 623
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
2.1
(1.8 to 2.3)
2.1
(1.9 to 2.4)
2.1
(1.9 to 2.3)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8426
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8264
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
10.Secondary Outcome
Title [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 308 281 0 308
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent Change
-5.6
(-5.9 to -5.4)
-5.7
(-5.9 to -5.4)
-5.0
(-5.2 to -4.7)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
11.Secondary Outcome
Title [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 32 46 0 33
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Fold Change
1.02
(0.96 to 1.08)
1.04
(0.99 to 1.09)
1.07
(1.01 to 1.13)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2138
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4330
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
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
Estimation Comments [Not Specified]
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)
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 20 10 0 14
Least Squares Mean (95% Confidence Interval)
Unit of Measure: SUVR
-0.02
(-0.04 to -0.01)
-0.04
(-0.06 to -0.03)
0.00
(-0.01 to 0.01)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0066
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value -0.03
Confidence Interval (2-Sided) 95%
-0.05 to 0.00
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value -0.04
Confidence Interval (2-Sided) 95%
-0.06 to -0.02
Estimation Comments [Not Specified]
13.Secondary Outcome
Title [Part I (Base Study)] Percentage of Participants Achieving Responder Status
Hide 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
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Hide 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]
Hide 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.
Overall Number of Participants Analyzed 652 652 0 653
Measure Type: Number
Unit of Measure: Percentage of Participants
20.1 19.6 19.3
14.Secondary Outcome
Title [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score
Hide 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
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Hide 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]
Hide 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.
Overall Number of Participants Analyzed 632 631 0 639
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
3.4
(2.5 to 4.4)
3.8
(2.8 to 4.8)
2.7
(1.7 to 3.7)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2949
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.6 to 2.1
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1372
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value 1.1
Confidence Interval (2-Sided) 95%
-0.4 to 2.6
Estimation Comments [Not Specified]
15.Secondary Outcome
Title [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score
Hide 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
Hide Outcome Measure Data
Hide 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]
Hide 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.
Overall Number of Participants Analyzed 610 600 0 628
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
-3.9
(-4.3 to -3.6)
-3.6
(-4.0 to -3.3)
-4.1
(-4.5 to -3.8)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4721
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-0.3 to 0.7
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0599
Comments [Not Specified]
Method Longitudinal ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Squares Means
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
0.0 to 1.0
Estimation Comments [Not Specified]
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]
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/702 (1.28%)      13/700 (1.86%)      3/103 (2.91%)      6/705 (0.85%)      6/379 (1.58%)      4/365 (1.10%)      4/61 (6.56%)      8/394 (2.03%)    
Show Serious Adverse Events Hide 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 (19.09%)      162/700 (23.14%)      24/103 (23.30%)      121/705 (17.16%)      57/379 (15.04%)      56/365 (15.34%)      22/61 (36.07%)      69/394 (17.51%)    
Blood and lymphatic system disorders                 
Anaemia  1  1/702 (0.14%)  1 0/700 (0.00%)  0 2/103 (1.94%)  2 0/705 (0.00%)  0 0/379 (0.00%)  0 2/365 (0.55%)  2 2/61 (3.28%)  2 0/394 (0.00%)  0
Haemorrhagic anaemia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Leukocytosis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Neutropenia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cardiac disorders                 
Acute coronary syndrome  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Acute myocardial infarction  1  0/702 (0.00%)  0 1/700 (0.14%)  2 0/103 (0.00%)  0 2/705 (0.28%)  2 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Angina unstable  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Arteriosclerosis coronary artery  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Atrial fibrillation  1  3/702 (0.43%)  3 2/700 (0.29%)  2 3/103 (2.91%)  3 1/705 (0.14%)  1 1/379 (0.26%)  1 2/365 (0.55%)  2 0/61 (0.00%)  0 1/394 (0.25%)  1
Bradycardia  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 2/365 (0.55%)  2 0/61 (0.00%)  0 0/394 (0.00%)  0
Cardiac arrest  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Cardiac failure  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Cardiac failure congestive  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 2/394 (0.51%)  2
Cardio-respiratory arrest  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Coronary artery disease  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Coronary artery occlusion  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Mitral valve incompetence  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Myocardial infarction  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Myocardial ischaemia  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Pericardial effusion  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Pericarditis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Sinus bradycardia  1  1/702 (0.14%)  1 2/700 (0.29%)  3 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Sinus node dysfunction  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Stress cardiomyopathy  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 2/365 (0.55%)  2 0/61 (0.00%)  0 0/394 (0.00%)  0
Torsade de pointes  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Conduction disorder  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Ear and labyrinth disorders                 
Deafness  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Meniere's disease  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Vertigo positional  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Endocrine disorders                 
Thyroid cyst  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Eye disorders                 
Cataract  1  1/702 (0.14%)  1 1/700 (0.14%)  2 0/103 (0.00%)  0 2/705 (0.28%)  2 0/379 (0.00%)  0 2/365 (0.55%)  3 0/61 (0.00%)  0 0/394 (0.00%)  0
Corneal oedema  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Glaucoma  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Keratitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Macular oedema  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Retinal detachment  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Trichiasis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Gastrointestinal disorders                 
Abdominal pain  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 2/394 (0.51%)  2
Abdominal pain lower  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Abdominal pain upper  1  2/702 (0.28%)  2 0/700 (0.00%)  0 1/103 (0.97%)  1 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Anal prolapse  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Colitis  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 2/365 (0.55%)  2 0/61 (0.00%)  0 0/394 (0.00%)  0
Diarrhoea  1  2/702 (0.28%)  2 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 3/394 (0.76%)  3
Diverticulum  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Diverticulum oesophageal  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Dysphagia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Enterocolitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Faecaloma  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Gastric ulcer  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Gastric ulcer haemorrhage  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Gastrointestinal haemorrhage  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Gastrooesophageal reflux disease  1  1/702 (0.14%)  1 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Haematemesis  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Haemorrhoids  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Ileus  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Incarcerated umbilical hernia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Inguinal hernia  1  1/702 (0.14%)  1 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Intestinal obstruction  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Large intestinal stenosis  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Large intestine perforation  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Large intestine polyp  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Melaena  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Nausea  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Oesophageal spasm  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Oesophagitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Pancreatitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Pancreatitis acute  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Retroperitoneal haematoma  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Small intestinal obstruction  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Vomiting  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
General disorders                 
Adverse drug reaction  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Asthenia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 2/705 (0.28%)  2 0/379 (0.00%)  0 1/365 (0.27%)  1 1/61 (1.64%)  1 0/394 (0.00%)  0
Chest discomfort  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Chest pain  1  1/702 (0.14%)  1 4/700 (0.57%)  4 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 2/365 (0.55%)  2 0/61 (0.00%)  0 1/394 (0.25%)  1
Death  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Drowning  1  1/702 (0.14%)  1 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Euthanasia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Gait disturbance  1  0/702 (0.00%)  0 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 1/379 (0.26%)  1 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
General physical health deterioration  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Incarcerated hernia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Malaise  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Mass  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Non-cardiac chest pain  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 2/705 (0.28%)  2 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Pyrexia  1  2/702 (0.28%)  2 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 3/394 (0.76%)  3
Systemic inflammatory response syndrome  1  0/702 (0.00%)  0 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Hepatobiliary disorders                 
Bile duct stone  1  2/702 (0.28%)  2 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Biliary colic  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cholangitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cholangitis acute  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Cholecystitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Cholecystitis chronic  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cholelithiasis  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Hepatic cyst  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Hepatitis acute  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Jaundice  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Immune system disorders                 
Anaphylactic reaction  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Hypersensitivity  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Infections and infestations                 
Anal abscess  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Appendicitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Bacteraemia  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Bronchitis  1  1/702 (0.14%)  1 1/700 (0.14%)  1 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Bronchitis viral  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cellulitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Clostridium difficile colitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Cystitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Diverticulitis  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 2/379 (0.53%)  2 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Erysipelas  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Escherichia urinary tract infection  1  0/702 (0.00%)  0 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Gallbladder empyema  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Gastroenteritis  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Gastroenteritis viral  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Gastrointestinal infection  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Haematoma infection  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Helicobacter gastritis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Influenza  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Lower respiratory tract infection  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Meningoencephalitis herpetic  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Neurosyphilis  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Osteomyelitis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Otitis media acute  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Periorbital cellulitis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Peritonitis  1  2/702 (0.28%)  2 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Pneumonia  1  5/702 (0.71%)  5 6/700 (0.86%)  6 3/103 (2.91%)  3 5/705 (0.71%)  5 3/379 (0.79%)  3 5/365 (1.37%)  5 3/61 (4.92%)  3 4/394 (1.02%)  4
Pyelonephritis  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Retroperitoneal infection  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Sepsis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Streptococcal sepsis  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Tuberculous pleurisy  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Upper respiratory tract infection  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Urinary tract infection  1  1/702 (0.14%)  1 1/700 (0.14%)  1 1/103 (0.97%)  1 2/705 (0.28%)  2 2/379 (0.53%)  2 1/365 (0.27%)  1 1/61 (1.64%)  1 0/394 (0.00%)  0
Urosepsis  1  3/702 (0.43%)  3 1/700 (0.14%)  1 0/103 (0.00%)  0 2/705 (0.28%)  2 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Injury, poisoning and procedural complications                 
Accidental overdose  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Anastomotic leak  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Ankle fracture  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 2/394 (0.51%)  2
Carbon monoxide poisoning  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Cervical vertebral fracture  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Comminuted fracture  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Concussion  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Contusion  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Facial bones fracture  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Fall  1  3/702 (0.43%)  3 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 2/365 (0.55%)  2 1/61 (1.64%)  1 0/394 (0.00%)  0
Femoral neck fracture  1  1/702 (0.14%)  1 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Femur fracture  1  1/702 (0.14%)  1 1/700 (0.14%)  1 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 2/365 (0.55%)  2 0/61 (0.00%)  0 2/394 (0.51%)  2
Fibula fracture  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 1/394 (0.25%)  1
Foot fracture  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Fracture displacement  1  0/702 (0.00%)  0 2/700 (0.29%)  2 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Hand fracture  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Head injury  1  0/702 (0.00%)  0 1/700 (0.14%)  1 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Hip fracture  1  0/702 (0.00%)  0 5/700 (0.71%)  5 1/103 (0.97%)  1 1/705 (0.14%)  1 2/379 (0.53%)  2 2/365 (0.55%)  2 2/61 (3.28%)  2 1/394 (0.25%)  1
Humerus fracture  1  2/702 (0.28%)  2 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Joint dislocation  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Laceration  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 1/61 (1.64%)  1 0/394 (0.00%)  0
Lumbar vertebral fracture  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Meniscus injury  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Multiple fractures  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 1/394 (0.25%)  1
Muscle strain  1  0/702 (0.00%)  0 0/700 (0.00%)  0 1/103 (0.97%)  1 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Prescribed overdose  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Radius fracture  1  0/702 (0.00%)  0 1/700 (0.14%)  1 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Rib fracture  1  1/702 (0.14%)  1 2/700 (0.29%)  2 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Skin abrasion  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Spinal compression fracture  1  1/702 (0.14%)  1 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Spinal fracture  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 1/379 (0.26%)  1 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Subarachnoid haemorrhage  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Subdural haematoma  1  2/702 (0.28%)  2 1/700 (0.14%)  1 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 1/365 (0.27%)  1 0/61 (0.00%)  0 0/394 (0.00%)  0
Subdural haemorrhage  1  1/702 (0.14%)  1 0/700 (0.00%)  0 0/103 (0.00%)  0 0/705 (0.00%)  0 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Thermal burn  1  0/702 (0.00%)  0 0/700 (0.00%)  0 0/103 (0.00%)  0 1/705 (0.14%)  1 0/379 (0.00%)  0 0/365 (0.00%)  0 0/61 (0.00%)  0 0/394 (0.00%)  0
Thoracic vertebral fracture  1