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An Efficacy and Safety Study of Lanabecestat (LY3314814) in Early Alzheimer's Disease (AMARANTH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02245737
Recruitment Status : Terminated (An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility)
First Posted : September 22, 2014
Results First Posted : August 6, 2019
Last Update Posted : December 3, 2019
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Alzheimer´s Disease
Interventions Drug: Lanabecestat
Drug: Placebo
Enrollment 2218
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Lanabecestat 20 Milligrams (mg) Lanabecestat 50 mg
Hide Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Period Title: Overall Study
Started 740 739 739
Received at Least 1 Dose of Study Drug 738 736 735
Completed 187 184 168
Not Completed 553 555 571
Reason Not Completed
Adverse Event             23             26             33
Condition Worsened             9             10             9
Death             2             4             4
Eligibility Criteria No Longer Met             2             4             4
Initiation of Symptomatic AD medication             2             0             0
Lost to Follow-up             2             5             4
Other-determined by Investigator             9             10             10
Physician Decision             6             3             6
Protocol Violation             3             2             3
Withdrawal by Subject             40             41             44
Withdrawal due to Caregiver Circumstance             10             20             22
Sponsor Decision             445             430             432
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg Total
Hide Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily. Total of all reporting groups
Overall Number of Baseline Participants 740 739 739 2218
Hide Baseline Analysis Population Description
All randomized participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
71.4  (6.9) 71.2  (7.5) 71.2  (7.0) 71.3  (7.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
Female
398
  53.8%
395
  53.5%
384
  52.0%
1177
  53.1%
Male
342
  46.2%
344
  46.5%
355
  48.0%
1041
  46.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
Hispanic or Latino
43
   5.8%
26
   3.5%
24
   3.2%
93
   4.2%
Not Hispanic or Latino
626
  84.6%
650
  88.0%
644
  87.1%
1920
  86.6%
Unknown or Not Reported
71
   9.6%
63
   8.5%
71
   9.6%
205
   9.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
85
  11.5%
85
  11.5%
102
  13.8%
272
  12.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
5
   0.7%
5
   0.7%
6
   0.8%
16
   0.7%
White
598
  80.8%
609
  82.4%
593
  80.2%
1800
  81.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
52
   7.0%
40
   5.4%
38
   5.1%
130
   5.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
Puerto Rico
13
   1.8%
11
   1.5%
12
   1.6%
36
   1.6%
Romania
1
   0.1%
2
   0.3%
2
   0.3%
5
   0.2%
Hungary
7
   0.9%
12
   1.6%
6
   0.8%
25
   1.1%
United States
171
  23.1%
171
  23.1%
179
  24.2%
521
  23.5%
Japan
48
   6.5%
57
   7.7%
78
  10.6%
183
   8.3%
United Kingdom
85
  11.5%
87
  11.8%
78
  10.6%
250
  11.3%
Spain
74
  10.0%
77
  10.4%
65
   8.8%
216
   9.7%
Canada
58
   7.8%
59
   8.0%
63
   8.5%
180
   8.1%
South Korea
30
   4.1%
24
   3.2%
16
   2.2%
70
   3.2%
Belgium
20
   2.7%
15
   2.0%
15
   2.0%
50
   2.3%
Poland
58
   7.8%
51
   6.9%
50
   6.8%
159
   7.2%
Italy
45
   6.1%
38
   5.1%
49
   6.6%
132
   6.0%
Australia
38
   5.1%
55
   7.4%
38
   5.1%
131
   5.9%
France
45
   6.1%
36
   4.9%
36
   4.9%
117
   5.3%
Germany
47
   6.4%
44
   6.0%
52
   7.0%
143
   6.4%
ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a Scale
Number Analyzed 740 participants 739 participants 739 participants 2218 participants
28.6  (7.9) 29.0  (7.7) 28.5  (8.2) 28.7  (8.0)
[1]
Measure Description: ADAS-Cog13, a 13-item rating scale, measured the severity of cognitive dysfunction in persons with Alzheimer's disease (AD). Scores ranged from 0 to 85, with a higher score indicating worse cognitive functioning.
1.Primary Outcome
Title Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
Hide Description ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 723 722 708
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
10.31  (0.55) 9.38  (0.56) 10.72  (0.58)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.232
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.93
Confidence Interval (2-Sided) 95%
-2.447 to 0.594
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.77
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.599
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.41
Confidence Interval (2-Sided) 95%
-1.124 to 1.947
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.78
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)
Hide Description The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADCS-iADL measure.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 702 700 674
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-8.87  (0.60) -8.84  (0.61) -8.79  (0.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.971
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-1.609 to 1.669
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.83
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.923
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.08
Confidence Interval (2-Sided) 95%
-1.580 to 1.743
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.85
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline on the Functional Activities Questionnaire (FAQ) Score
Hide Description FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did [the activity] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). FAQ scale is 0 to 30, with higher scores indicating greater impairment. LS Mean was calculated by MMRM with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline and pooled country.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for FAQ score.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 699 697 674
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
6.09  (0.38) 5.96  (0.39) 6.71  (0.40)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.796
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.14
Confidence Interval (2-Sided) 95%
-1.172 to 0.899
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.53
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.252
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
-0.437 to 1.660
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.53
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score
Hide Description The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS- Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by- visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for iADRS.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 696 689 662
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-19.56  (0.99) -18.45  (1.02) -19.69  (1.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.428
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 1.11
Confidence Interval (2-Sided) 95%
-1.637 to 3.852
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.40
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.926
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-2.918 to 2.655
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.42
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
Hide Description The CDR-SB is a rater administered scale and impairment is scored in of the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR-SB.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 704 705 676
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
3.02  (0.17) 3.17  (0.17) 3.17  (0.18)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.533
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.15
Confidence Interval (2-Sided) 95%
-0.322 to 0.622
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.24
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.537
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.15
Confidence Interval (2-Sided) 95%
-0.328 to 0.630
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.24
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage
Hide Description The CDR global score is a composite score calculated using the Washington University CDR-assignment algorithm applied to the 6 individual domain box scores (Morris 1993). The memory domain is considered the primary category that drives the CDR global outcome, and all other domains are secondary. The CDR global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia).
Time Frame Baseline through Loss of 1 Global Stage or Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR Global Score.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 716 714 696
Median (95% Confidence Interval)
Unit of Measure: Days
548
(547 to 554)
547
(545 to 550)
548
(545 to 553)
7.Secondary Outcome
Title Change From Baseline in Neuropsychiatric Inventory (NPI) Score
Hide Description The NPI is a questionnaire administered to caregivers that quantifies behavioral changes. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144, with higher scores indicating greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline NPI score, age at baseline, and baseline NPI score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for NPI.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 697 695 663
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
3.22  (0.81) 4.99  (0.83) 4.67  (0.85)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.116
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 1.77
Confidence Interval (2-Sided) 95%
-0.441 to 3.986
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.13
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.208
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 1.45
Confidence Interval (2-Sided) 95%
-0.808 to 3.704
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.15
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline on the Mini-Mental State Examination (MMSE)
Hide Description The MMSE is an instrument used to assess a participant's global cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with a higher score indicating better cognitive performance. LS mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for MMSE.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 723 725 709
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-5.50  (0.26) -5.18  (0.26) -5.49  (0.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.379
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.32
Confidence Interval (2-Sided) 95%
-0.391 to 1.027
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.36
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.992
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.714 to 0.721
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.37
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42
Hide Description Concentration of the peptide Aβ 1-42 in plasma measured by validated immunoassay. LS Mean was determined by Analysis of covariance (ANCOVA) with last observation carried forward (LOCF), terms for treatment, baseline biomarker and age at baseline.
Time Frame Baseline, Week 97
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-42.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 63 66 79
Least Squares Mean (Standard Error)
Unit of Measure: Percent change in Aβ1-42
-2.64  (2.07) -53.91  (2.04) -68.13  (1.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -51.27
Confidence Interval (2-Sided) 95%
-56.963 to -45.578
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.89
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -65.48
Confidence Interval (2-Sided) 95%
-70.947 to -60.022
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.77
Estimation Comments [Not Specified]
10.Secondary Outcome
Title PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40
Hide Description Concentration of the peptide Aβ 1-40 in plasma measured by immunoassay. LS Mean was determined by ANCOVA with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline.
Time Frame Baseline, Week 97
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-40.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 64 66 79
Least Squares Mean (Standard Error)
Unit of Measure: Percent change in Aβ1-40
-1.92  (1.77) -59.90  (1.74) -75.17  (1.60)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -57.99
Confidence Interval (2-Sided) 95%
-62.865 to -53.108
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.47
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -73.25
Confidence Interval (2-Sided) 95%
-77.926 to -68.575
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.37
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline in CSF Total Tau
Hide Description Cerebrospinal fluid samples are collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame Baseline, Week 97
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Total Tau.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 64 66 79
Least Squares Mean (Standard Error)
Unit of Measure: Picogram per milliliter (pg/mL)
12.39  (8.05) -7.48  (8.01) -2.92  (7.30)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.081
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -19.87
Confidence Interval (2-Sided) 95%
-42.210 to 2.464
Parameter Dispersion
Type: Standard Error of the Mean
Value: 11.33
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.157
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -15.31
Confidence Interval (2-Sided) 95%
-36.555 to 5.938
Parameter Dispersion
Type: Standard Error of the Mean
Value: 10.78
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change From Baseline in CSF Phosphorylated Tau
Hide Description Cerebrospinal fluid samples are collected for analysis of concentrations of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame Baseline, Week 97
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Phosphorylated Tau.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 63 66 79
Least Squares Mean (Standard Error)
Unit of Measure: Picogram per milliliter (pg/mL)
0.47  (0.95) -2.16  (0.94) -1.66  (0.85)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.050
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -2.62
Confidence Interval (2-Sided) 95%
-5.243 to -0.002
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.33
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.095
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -2.12
Confidence Interval (2-Sided) 95%
-4.618 to 0.373
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.27
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan
Hide Description Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease. Florbetapir exhibits high affinity specific binding to amyloid plaques. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by florbetapir amyloid PET imaging in a subset of participants. The Centiloid scale standardizes quantitative brain amyloid PET results to allow cross-tracer and cross-methodology comparisons. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. Florbetapir SUVr was converted to the Centiloid scale using the following conversion: Florbetapir Centiloids = 183 x SUVr - 177. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for brain amyloid burden.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 133 127 116
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-2.08  (1.86) -15.76  (1.89) -19.74  (1.97)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -13.68
Confidence Interval (2-Sided) 95%
-18.785 to -8.574
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.60
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -17.66
Confidence Interval (2-Sided) 95%
-22.887 to -12.428
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.66
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Change From Baseline in Tau PET ((Flortaucipir F18)
Hide Description Tau PET tracer (flortaucipir F18) longitudinal study measured whether lanabecestat, in participants with mild AD dementia, affected tau density and distribution over time. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the signal intensity in white matter. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Tau PET.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 97 94 93
Least Squares Mean (Standard Error)
Unit of Measure: Standard Uptake Value ratio (SUVr)
0.04  (0.01) 0.03  (0.01) 0.03  (0.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.426
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.033 to 0.014
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.01
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.660
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.029 to 0.018
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.01
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)
Hide Description Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the pons + vermis assessed with composite meta and composite meta automated anatomical labeling atlas (ALL). Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data of brain metabolism.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 83 95 82
Least Squares Mean (Standard Error)
Unit of Measure: Standard Uptake Value ratio (SUVr)
-0.04  (0.00) -0.05  (0.00) -0.05  (0.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.210
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.015 to 0.003
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.568
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.00
Confidence Interval (2-Sided) 95%
-0.013 to 0.007
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.00
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Change From Baseline in Whole Brain Volume
Hide Description Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on whole brain volumes. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, baseline vMRI, intracranial volume, disease status at baseline and age at baseline.
Time Frame Baseline, Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Whole Brain Volume.
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received placebo film-coated oral tablets once daily.
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 565 582 550
Least Squares Mean (Standard Error)
Unit of Measure: cm^3 (cubic centimeter)
-14.16  (0.34) -16.49  (0.33) -17.34  (0.34)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -2.34
Confidence Interval (2-Sided) 95%
-3.258 to -1.413
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.47
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -3.18
Confidence Interval (2-Sided) 95%
-4.118 to -2.247
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.48
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Pharmacokinetics (PK): Plasma Concentration of Lanabecestat
Hide Description [Not Specified]
Time Frame Week 4, post dose prior to departure from the clinic
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and have evaluable PK data.
Arm/Group Title Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description:
Participants received lanabecestat 20 mg film-coated oral tablets once daily.
Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed 697 662
Mean (Standard Deviation)
Unit of Measure: nanograms per milliliter (ng/mL)
67.7  (49.1) 213  (149)
Time Frame Up To 104 weeks
Adverse Event Reporting Description All randomized participants who received at least one dose of study drug. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
 
Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Hide Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
All-Cause Mortality
Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/738 (0.27%)      4/736 (0.54%)      4/735 (0.54%)    
Hide Serious Adverse Events
Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   108/738 (14.63%)      117/736 (15.90%)      147/735 (20.00%)    
Blood and lymphatic system disorders       
Anaemia  1  2/738 (0.27%)  3 1/736 (0.14%)  1 1/735 (0.14%)  1
Cardiac disorders       
Acute coronary syndrome  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Acute myocardial infarction  1  2/738 (0.27%)  3 0/736 (0.00%)  0 2/735 (0.27%)  2
Angina pectoris  1  2/738 (0.27%)  2 1/736 (0.14%)  1 1/735 (0.14%)  1
Angina unstable  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Atrial fibrillation  1  2/738 (0.27%)  3 2/736 (0.27%)  2 1/735 (0.14%)  1
Atrial flutter  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Bifascicular block  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Bradycardia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Cardiac failure  1  0/738 (0.00%)  0 2/736 (0.27%)  2 2/735 (0.27%)  2
Cardiac tamponade  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Cardio-respiratory arrest  1  2/738 (0.27%)  2 1/736 (0.14%)  1 0/735 (0.00%)  0
Coronary artery disease  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Coronary artery thrombosis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Myocardial infarction  1  4/738 (0.54%)  4 2/736 (0.27%)  2 0/735 (0.00%)  0
Sinus bradycardia  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Sinus node dysfunction  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Stress cardiomyopathy  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Supraventricular extrasystoles  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Supraventricular tachycardia  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Tachycardia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Tricuspid valve incompetence  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Congenital, familial and genetic disorders       
Gastrointestinal arteriovenous malformation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Ear and labyrinth disorders       
Vestibular disorder  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Eye disorders       
Cataract  1  0/738 (0.00%)  0 2/736 (0.27%)  2 1/735 (0.14%)  2
Pterygium  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Retinal detachment  1  2/738 (0.27%)  2 0/736 (0.00%)  0 0/735 (0.00%)  0
Retinal haemorrhage  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Alcoholic pancreatitis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Anal incontinence  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  2
Coeliac artery stenosis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Colitis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Colitis microscopic  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Constipation  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  1
Diarrhoea  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Enlarged uvula  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Faecaloma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Femoral hernia incarcerated  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Food poisoning  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Gastric ulcer  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Gastritis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Gastrointestinal haemorrhage  1  2/738 (0.27%)  2 1/736 (0.14%)  1 1/735 (0.14%)  1
Gastrooesophageal reflux disease  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Haemorrhoids  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Inguinal hernia  1  1/738 (0.14%)  1 2/736 (0.27%)  2 3/735 (0.41%)  3
Intestinal mass  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Intestinal obstruction  1  0/738 (0.00%)  0 0/736 (0.00%)  0 3/735 (0.41%)  3
Large intestine polyp  1  0/738 (0.00%)  0 1/736 (0.14%)  2 2/735 (0.27%)  2
Lower gastrointestinal haemorrhage  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Pancreatitis acute  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Rectal prolapse  1  0/738 (0.00%)  0 2/736 (0.27%)  3 0/735 (0.00%)  0
Small intestinal obstruction  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Vomiting  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
General disorders       
Asthenia  1  1/738 (0.14%)  1 1/736 (0.14%)  1 1/735 (0.14%)  1
Chest pain  1  1/738 (0.14%)  1 4/736 (0.54%)  4 4/735 (0.54%)  4
Non-cardiac chest pain  1  1/738 (0.14%)  1 2/736 (0.27%)  2 1/735 (0.14%)  1
Pyrexia  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Sudden death  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Systemic inflammatory response syndrome  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hepatobiliary disorders       
Cholelithiasis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Drug-induced liver injury  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Seasonal allergy  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Infections and infestations       
Appendicitis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Bone abscess  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Bronchitis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Cellulitis  1  1/738 (0.14%)  1 1/736 (0.14%)  1 2/735 (0.27%)  2
Clostridium difficile colitis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Diverticulitis  1  1/738 (0.14%)  1 1/736 (0.14%)  1 3/735 (0.41%)  4
Endocarditis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hepatic cyst infection  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Human anaplasmosis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Infection  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Influenza  1  0/738 (0.00%)  0 2/736 (0.27%)  2 4/735 (0.54%)  4
Intervertebral discitis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Lower respiratory tract infection  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Lower respiratory tract infection viral  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Ophthalmic herpes zoster  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Peritonsillitis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Pneumonia  1  6/738 (0.81%)  6 3/736 (0.41%)  3 3/735 (0.41%)  3
Sepsis  1  2/738 (0.27%)  2 0/736 (0.00%)  0 1/735 (0.14%)  1
Septic arthritis streptococcal  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Septic shock  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  1
Urinary tract infection  1  6/738 (0.81%)  8 1/736 (0.14%)  1 3/735 (0.41%)  3
Urinary tract infection pseudomonal  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Vestibular neuronitis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Injury, poisoning and procedural complications       
Accidental overdose  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Accidental poisoning  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Alcohol poisoning  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Ankle fracture  1  1/738 (0.14%)  1 1/736 (0.14%)  1 1/735 (0.14%)  1
Cervical vertebral fracture  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Chemical burn of gastrointestinal tract  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Clavicle fracture  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Contusion  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Fall  1  6/738 (0.81%)  6 8/736 (1.09%)  8 4/735 (0.54%)  4
Femoral neck fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 2/735 (0.27%)  2
Femur fracture  1  1/738 (0.14%)  1 2/736 (0.27%)  2 1/735 (0.14%)  1
Fibula fracture  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  1
Forearm fracture  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Head injury  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  1
Hip fracture  1  0/738 (0.00%)  0 3/736 (0.41%)  3 2/735 (0.27%)  2
Humerus fracture  1  1/738 (0.14%)  2 0/736 (0.00%)  0 2/735 (0.27%)  2
Jaw fracture  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Lacrimal structure injury  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Ligament rupture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Lumbar vertebral fracture  1  2/738 (0.27%)  2 0/736 (0.00%)  0 1/735 (0.14%)  1
Multiple injuries  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Overdose  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Pelvic fracture  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Periprosthetic fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Post procedural haemorrhage  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Pubis fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Radius fracture  1  1/738 (0.14%)  1 1/736 (0.14%)  1 2/735 (0.27%)  2
Rib fracture  1  2/738 (0.27%)  2 0/736 (0.00%)  0 0/735 (0.00%)  0
Road traffic accident  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Skin laceration  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Skull fracture  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Spinal compression fracture  1  3/738 (0.41%)  3 0/736 (0.00%)  0 1/735 (0.14%)  1
Spinal fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Subdural haematoma  1  3/738 (0.41%)  3 0/736 (0.00%)  0 3/735 (0.41%)  4
Subdural haemorrhage  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Thoracic vertebral fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Tibia fracture  1  2/738 (0.27%)  2 0/736 (0.00%)  0 1/735 (0.14%)  1
Ulna fracture  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  1
Upper limb fracture  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Wrist fracture  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Investigations       
Blood potassium decreased  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Dehydration  1  1/738 (0.14%)  1 4/736 (0.54%)  4 5/735 (0.68%)  5
Electrolyte imbalance  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hypercalcaemia  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hyperglycaemia  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Hypoglycaemia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Hypokalaemia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Hyponatraemia  1  0/738 (0.00%)  0 2/736 (0.27%)  2 1/735 (0.14%)  1
Hypophosphataemia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Lactic acidosis  1  2/738 (0.27%)  2 0/736 (0.00%)  0 0/735 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthritis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 2/735 (0.27%)  2
Back pain  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Bone lesion  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Foot deformity  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Infrapatellar fat pad inflammation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Intervertebral disc compression  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Intervertebral disc protrusion  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Lumbar spinal stenosis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 1/735 (0.14%)  2
Mobility decreased  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Musculoskeletal chest pain  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Musculoskeletal pain  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Myofascial pain syndrome  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Osteoarthritis  1  4/738 (0.54%)  4 2/736 (0.27%)  2 1/735 (0.14%)  1
Osteolysis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Osteoporotic fracture  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Pain in extremity  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Spinal column stenosis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Vertebral foraminal stenosis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acoustic neuroma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Acute myeloid leukaemia  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Adenocarcinoma of colon  1  1/738 (0.14%)  1 1/736 (0.14%)  1 1/735 (0.14%)  1
Basal cell carcinoma  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Bile duct adenocarcinoma  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Bladder neoplasm  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Breast cancer  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Breast cancer male  1  0/341 (0.00%)  0 1/344 (0.29%)  1 0/354 (0.00%)  0
Breast cancer recurrent  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Colon cancer  1  0/738 (0.00%)  0 0/736 (0.00%)  0 2/735 (0.27%)  2
Endometrial adenocarcinoma  1  1/397 (0.25%)  1 0/392 (0.00%)  0 0/381 (0.00%)  0
Haemangioma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Invasive ductal breast carcinoma  1  0/738 (0.00%)  0 2/736 (0.27%)  2 2/735 (0.27%)  2
Laryngeal squamous cell carcinoma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Lentigo maligna  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Lung adenocarcinoma  1  2/738 (0.27%)  2 0/736 (0.00%)  0 3/735 (0.41%)  3
Lung neoplasm  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Lung neoplasm malignant  1  0/738 (0.00%)  0 2/736 (0.27%)  2 0/735 (0.00%)  0
Lymphoma  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Malignant melanoma  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Malignant melanoma in situ  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Malignant neoplasm of unknown primary site  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Metastases to bone  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Metastases to lymph nodes  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Neuroendocrine tumour  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Ovarian adenoma  1  0/397 (0.00%)  0 0/392 (0.00%)  0 1/381 (0.26%)  1
Pancreatic carcinoma  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Prostate cancer  1  2/341 (0.59%)  2 2/344 (0.58%)  2 2/354 (0.56%)  2
Prostatic adenoma  1  1/341 (0.29%)  1 0/344 (0.00%)  0 0/354 (0.00%)  0
Rectal adenocarcinoma  1  1/738 (0.14%)  1 1/736 (0.14%)  1 0/735 (0.00%)  0
Rectal adenoma  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Rectal cancer  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Small cell lung cancer  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Squamous cell carcinoma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Transitional cell carcinoma  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Nervous system disorders       
Altered state of consciousness  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Central nervous system lesion  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Cerebral haematoma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Cerebral haemorrhage  1  3/738 (0.41%)  3 0/736 (0.00%)  0 2/735 (0.27%)  2
Cerebral microhaemorrhage  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Cerebrovascular accident  1  2/738 (0.27%)  2 3/736 (0.41%)  3 1/735 (0.14%)  1
Cervical radiculopathy  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Cholinergic syndrome  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Cognitive disorder  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Dementia with lewy bodies  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Dizziness  1  1/738 (0.14%)  1 1/736 (0.14%)  1 1/735 (0.14%)  1
Dyskinesia  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Epilepsy  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Generalised tonic-clonic seizure  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Headache  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hypertensive encephalopathy  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hypoaesthesia  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Intraventricular haemorrhage  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Partial seizures  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Petit mal epilepsy  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Presyncope  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Sciatica  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Seizure  1  0/738 (0.00%)  0 1/736 (0.14%)  1 2/735 (0.27%)  2
Subarachnoid haemorrhage  1  2/738 (0.27%)  2 1/736 (0.14%)  1 0/735 (0.00%)  0
Syncope  1  2/738 (0.27%)  2 6/736 (0.82%)  6 7/735 (0.95%)  7
Thalamic infarction  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Transient ischaemic attack  1  2/738 (0.27%)  2 2/736 (0.27%)  2 2/735 (0.27%)  2
Ulnar nerve palsy  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Vasogenic cerebral oedema  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Vocal cord paresis  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Product Issues       
Device failure  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Psychiatric disorders       
Abnormal behaviour  1  2/738 (0.27%)  2 1/736 (0.14%)  1 1/735 (0.14%)  1
Acute psychosis  1  0/738 (0.00%)  0 2/736 (0.27%)  2 0/735 (0.00%)  0
Aggression  1  1/738 (0.14%)  1 1/736 (0.14%)  1 2/735 (0.27%)  2
Agitation  1  2/738 (0.27%)  2 0/736 (0.00%)  0 2/735 (0.27%)  2
Anxiety  1  0/738 (0.00%)  0 0/736 (0.00%)  0 2/735 (0.27%)  2
Confusional state  1  2/738 (0.27%)  2 1/736 (0.14%)  1 0/735 (0.00%)  0
Delirium  1  1/738 (0.14%)  1 2/736 (0.27%)  2 5/735 (0.68%)  5
Depression  1  0/738 (0.00%)  0 0/736 (0.00%)  0 4/735 (0.54%)  4
Depressive symptom  1  0/738 (0.00%)  0 0/736 (0.00%)  0 3/735 (0.41%)  3
Hallucination  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Hallucination, auditory  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Hallucination, olfactory  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Paranoia  1  2/738 (0.27%)  2 0/736 (0.00%)  0 0/735 (0.00%)  0
Psychotic disorder  1  2/738 (0.27%)  2 0/736 (0.00%)  0 0/735 (0.00%)  0
Schizophrenia  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Suicidal ideation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Suicide attempt  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Renal and urinary disorders       
Acute kidney injury  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Calculus bladder  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Urge incontinence  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Urinary retention  1  0/738 (0.00%)  0 1/736 (0.14%)  1 1/735 (0.14%)  1
Reproductive system and breast disorders       
Benign prostatic hyperplasia  1  2/341 (0.59%)  2 1/344 (0.29%)  1 1/354 (0.28%)  1
Postmenopausal haemorrhage  1  0/397 (0.00%)  0 1/392 (0.26%)  1 0/381 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute respiratory distress syndrome  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Asthma  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Cystic lung disease  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Dyspnoea  1  0/738 (0.00%)  0 2/736 (0.27%)  2 1/735 (0.14%)  1
Obstructive airways disorder  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Pneumonia aspiration  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Pneumothorax  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Pulmonary embolism  1  0/738 (0.00%)  0 1/736 (0.14%)  1 2/735 (0.27%)  2
Pulmonary oedema  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Respiratory arrest  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Sleep apnoea syndrome  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Stridor  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Skin and subcutaneous tissue disorders       
Angioedema  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Drug eruption  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Psoriasis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Surgical and medical procedures       
Cardiac pacemaker insertion  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Cataract operation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Hip arthroplasty  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Inguinal hernia repair  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Spinal operation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Synovial cyst removal  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Tumour excision  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Urethral repair  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Vocal cord operation  1  0/738 (0.00%)  0 1/736 (0.14%)  1 0/735 (0.00%)  0
Vascular disorders       
Aortic aneurysm  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Deep vein thrombosis  1  0/738 (0.00%)  0 2/736 (0.27%)  2 0/735 (0.00%)  0
Granulomatosis with polyangiitis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Haematoma  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Hypertension  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Hypertensive crisis  1  1/738 (0.14%)  1 0/736 (0.00%)  0 0/735 (0.00%)  0
Hypotension  1  2/738 (0.27%)  2 1/736 (0.14%)  1 1/735 (0.14%)  1
Orthostatic hypotension  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Peripheral artery stenosis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Temporal arteritis  1  0/738 (0.00%)  0 2/736 (0.27%)  2 0/735 (0.00%)  0
Thrombophlebitis  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
Venous thrombosis limb  1  0/738 (0.00%)  0 0/736 (0.00%)  0 1/735 (0.14%)  1
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Lanabecestat 20 mg Lanabecestat 50 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   340/738 (46.07%)      357/736 (48.51%)      361/735 (49.12%)    
Gastrointestinal disorders       
Diarrhoea  1  39/738 (5.28%)  44 62/736 (8.42%)  81 54/735 (7.35%)  62
Nausea  1  32/738 (4.34%)  38 33/736 (4.48%)  39 41/735 (5.58%)  50
Infections and infestations       
Nasopharyngitis  1  60/738 (8.13%)  69 78/736 (10.60%)  94 76/735 (10.34%)  89
Upper respiratory tract infection  1  46/738 (6.23%)  57 39/736 (5.30%)  43 44/735 (5.99%)  50
Urinary tract infection  1  56/738 (7.59%)  70 36/736 (4.89%)  53 32/735 (4.35%)  36
Injury, poisoning and procedural complications       
Fall  1  69/738 (9.35%)  86 71/736 (9.65%)  95 73/735 (9.93%)  111
Musculoskeletal and connective tissue disorders       
Back pain  1  40/738 (5.42%)  50 36/736 (4.89%)  38 33/735 (4.49%)  35
Nervous system disorders       
Dizziness  1  42/738 (5.69%)  48 43/736 (5.84%)  52 51/735 (6.94%)  61
Headache  1  52/738 (7.05%)  56 40/736 (5.43%)  50 46/735 (6.26%)  72
Psychiatric disorders       
Anxiety  1  34/738 (4.61%)  40 57/736 (7.74%)  63 48/735 (6.53%)  50
Depression  1  31/738 (4.20%)  32 36/736 (4.89%)  39 46/735 (6.26%)  49
Respiratory, thoracic and mediastinal disorders       
Cough  1  25/738 (3.39%)  25 46/736 (6.25%)  49 25/735 (3.40%)  29
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The sponsor shall review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60days but less than or equal to 180days from the time submitted to the sponsor.Authors agree not to publish results until data is compiled. No publication/presentation with respect to the research activities shall be made unless & until any information determined at sponsors sole discretion to be confidential information has been removed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: AstraZeneca Information Center
Organization: AstraZeneca
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02245737    
Other Study ID Numbers: 16023
I8D-MC-AZES ( Other Identifier: Eli Lilly and Company )
2014-002601-38 ( EudraCT Number )
D5010C00009 ( Other Identifier: AstraZeneca )
First Submitted: September 18, 2014
First Posted: September 22, 2014
Results First Submitted: June 11, 2019
Results First Posted: August 6, 2019
Last Update Posted: December 3, 2019