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ENGAGE: 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease

Sponsor
Biogen (Industry)
Overall Status
Terminated
CT.gov ID
NCT02477800
Collaborator
(none)
1,653
Enrollment
181
Locations
2
Arms
47.8
Actual Duration (Months)
9.1
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with early AD. Secondary objectives are to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale (13 items) [ADAS-Cog 13], and AD Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) [ADCS-ADL-MCI].

Condition or Disease Intervention/Treatment Phase
  • Drug: Aducanumab (BIIB037)
  • Drug: Aducanumab (BIIB037)
  • Drug: Placebo
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
1653 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease
Actual Study Start Date :
Aug 13, 2015
Actual Primary Completion Date :
Aug 8, 2019
Actual Study Completion Date :
Aug 8, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Low Dose

Monthly intravenous (IV) infusion

Drug: Aducanumab (BIIB037)
Low dose

Drug: Placebo
Placebo
Experimental: High Dose

Monthly intravenous (IV) infusion

Drug: Aducanumab (BIIB037)
High dose

Drug: Placebo
Placebo

Outcome Measures

Primary Outcome Measures

  1. Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 78 [Baseline, Week 78]

    CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic patient examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. Prespecified severity anchors range from none = 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). "Sum of boxes" scoring methodology sums the score for each of the 6 domains and provides a value ranging from 0 to 18 that can change in increments of 0.5 or greater. Higher scores indicate greater disease severity. Mixed model for repeated measures (MMRM) analysis was used to analyze change from baseline in CDR-SB. A positive change from baseline indicates clinical decline.

Secondary Outcome Measures

  1. Change From Baseline in Mini-Mental State Examination (MMSE) Score at Week 78 [Baseline, Week 78]

    The MMSE is a widely used performance-based test of global cognitive status. It consists of 11 tasks that assess orientation, word recall, attention and calculation, language abilities, and visuospatial functions. The scores from the 11 tests are combined to obtain the total score, which ranges from 0 to 30, with lower scores over time indicating increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in MMSE. A negative change from baseline indicates clinical decline.

  2. Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) Score at Week 78 [Baseline, Week 78]

    ADAS-Cog13 comprises both cognitive tasks and clinical ratings of cognitive performance. The scale items capture word recall, ability to follow commands, the ability to correctly copy or draw an image, naming, the ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure for delayed word recall and concentration/distractibility. The total score ranges from 0 to 85. An increase in score over time indicates increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in ADAS-Cog 13. A positive change from baseline indicates clinical decline.

  3. Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL-MCI) Score at Week 78 [Baseline, Week 78]

    The ADCS-ADL-MCI consists of 17 instrumental items (e.g., shopping, preparing meals, using household appliances) and 1 basic item (getting dressed). Ratings reflect caregiver observations about the patient's actual functioning over the previous month and provide an assessment of change in the functional state of the participant over time. The total score ranges from 0 to 53, with lower values over time reflecting functional deterioration. MMRM analysis was used to analyze change from baseline in ADAS-ADL-MCI. A negative change from baseline indicates clinical decline.

Eligibility Criteria

Criteria

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

  • Must meet all of the following clinical criteria for MCI due to AD or mild AD and must have:

  • A Clinical Dementia Rating (CDR)-Global Score of 0.5.

  • Objective evidence of cognitive impairment at screening

  • An MMSE score between 24 and 30 (inclusive)

  • Must have a positive amyloid Positron Emission Tomography (PET) scan

  • Must consent to apolipoprotein E (ApoE) genotyping

  • If using drugs to treat symptoms related to AD, doses must be stable for at least 8 weeks prior to screening visit 1

  • Must have a reliable informant or caregiver

Key Exclusion Criteria:

  • Any medical or neurological condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment

  • Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year

  • Clinically significant unstable psychiatric illness in past 6 months

  • History of unstable angina, myocardial infarction, advanced chronic heart failure, or clinically significant conduction abnormalities within 1 year prior to Screening

  • Indication of impaired renal or liver function

  • Have human immunodeficiency virus (HIV) infection

  • Have a significant systematic illness or infection in past 30 days

  • Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities

  • Any contraindications to brain magnetic resonance imaging (MRI) or PET scans

  • Alcohol or substance abuse in past 1 year

  • Taking blood thinners (except for aspirin at a prophylactic dose or less)

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

Site City State Country Postal Code
1 St. Joseph's Hospital and Medical Center Phoenix Arizona United States 85013
2 Center for Neurosciences Tucson Arizona United States 85718
3 Neurology Center of North Orange County Fullerton California United States 92835
4 Senior Clinical Trials, Inc. Laguna Hills California United States 92653
5 Torrance Clinical Research Institute, Inc. Lomita California United States 90717
6 University of California - Los Angeles Los Angeles California United States 90095
7 UCSF - Memory and Aging Center San Francisco California United States 94158
8 California Neuroscience Research Medical Group Inc. Sherman Oaks California United States 91403
9 Southern California Research LLC Simi Valley California United States 93065
10 Institute for Neurodegenerative Disorders New Haven Connecticut United States 06510
11 Georgetown University Hospital Washington District of Columbia United States 20057
12 Brain Matters Research, Inc. Delray Beach Florida United States 33445
13 Neuropsychiatric Research Center of Southwest Florida Fort Myers Florida United States 33912
14 Jacksonville Center for Clinical Research Jacksonville Florida United States 32216
15 University of Miami Miami Florida United States 33136
16 Miami Jewish Health Systems Miami Florida United States 33137
17 Compass Research Main Orlando Florida United States 32806
18 Palm Beach Neurological Center Palm Beach Gardens Florida United States 33410
19 Stedman Clinical Trials, LLC Tampa Florida United States 33613
20 USF Health Byrd Institute Tampa Florida United States 33616
21 Meridien Research Tampa Florida United States 33634
22 Compass Research Main The Villages Florida United States 32162
23 Premiere Research Institute West Palm Beach Florida United States 33407
24 Cleveland Clinic Florida - Weston Weston Florida United States 33331
25 Alexian Brothers Neurosciences Institute Elk Grove Village Illinois United States 60007
26 Advocate Lutheran General Hospital Park Ridge Illinois United States 60068
27 Fort Wayne Neurological Center Fort Wayne Indiana United States 46804
28 Indiana University School of Medicine Indianapolis Indiana United States 46202
29 University of Kansas Medical Center Research Institute, Inc. Kansas City Kansas United States 66160
30 Via Christi Research, a division of Via Christi Hospitals Wichita, Inc. Wichita Kansas United States 67214
31 Baptist Health Lexington Lexington Kentucky United States 40503
32 Brigham & Women's Hosp End/Dbt Boston Massachusetts United States 02115
33 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
34 ActivMed Practices & Research Methuen Massachusetts United States 01844
35 Donald S. Marks, M.D., P.C. Plymouth Massachusetts United States 02360
36 Mayo Clinic Rochester Minnesota United States 55905
37 Washington University Saint Louis Missouri United States 63131
38 Las Vegas Medical research Las Vegas Nevada United States 89113
39 Advanced Memory Research Institute of NJ, PC Toms River New Jersey United States 08755
40 Albany Medical College Albany New York United States 12208
41 New York University Medical Center PRIME New York New York United States 10016
42 University of Rochester Rochester New York United States 14620
43 ANI Neurology, PLLC d/b/a Alzheimer's Memory Center Charlotte North Carolina United States 28270
44 Raleigh Neurology Associates, P.A. Raleigh North Carolina United States 27607-6010
45 Cleveland Clinic Cleveland Ohio United States 44195
46 Lynn Health Science Institute Oklahoma City Oklahoma United States 73112
47 The Clinical Trial Center, LLC Jenkintown Pennsylvania United States 19046
48 University of Pittsburgh Pittsburgh Pennsylvania United States 15213
49 Northeastern Pennsylvania Memory and Alzheimer's Center Plains Pennsylvania United States 18705
50 Rhode Island Mood & Memory Research Institute East Providence Rhode Island United States 02915
51 Butler Hospital Providence Rhode Island United States 02906
52 Medical University of South Carolina (MUSC) Charleston South Carolina United States 29425
53 Neurology Clinic, PC Cordova Tennessee United States 38108
54 University of Tennessee Medical Center. Knoxville Knoxville Tennessee United States 37920
55 Clinical Neuroscience Solutions, Inc. Memphis Tennessee United States 38119
56 UT Southwestern Medical Center at Dallas Dallas Texas United States 75390
57 Baylor College of Medicine Houston Texas United States 77030
58 National Clinical Research Inc.-Richmond Richmond Virginia United States 23294
59 Medical College of Wisconsin, Inc. Milwaukee Wisconsin United States 53266
60 St Vincent's Hospital Sydney Darlinghurst New South Wales Australia 2010
61 Central Coast Neurosciences Research, Gosford East Gosford New South Wales Australia 2250
62 Central Coast Neurosciences Research Erina New South Wales Australia 2250
63 KARA Institute for Neurological Diseases North Ryde New South Wales Australia 2113
64 Calvary Mater Newcastle Waratah New South Wales Australia 2298
65 The Prince Charles Hospital Chermside Queensland Australia 4032
66 Royal Brisbane and Women's Hospital Herston Queensland Australia 4006
67 Toowoomba Base Hospital Toowoomba Queensland Australia 4350
68 Box Hill Hospital Box Hill Victoria Australia 3128
69 Austin Hospital Heidelberg Victoria Australia 3084
70 Royal Melbourne Hospital Parkville Victoria Australia 3050
71 Neurodegenerative Disorders Research West Perth Western Australia Australia 6005
72 LKH - Universitaetsklinikum Graz Graz Austria 8036
73 Christian-Doppler-Klinik - Universitätsklinikum Salzburg Salzburg Austria 5020
74 Heritage Medical Research Clinic Calgary Alberta Canada T2N 1N4
75 The Medical Arts Health Research Group Penticton British Columbia Canada V2A 5C8
76 UBC Hospital Vancouver British Columbia Canada V6T 2B5
77 Toronto Memory Program (Neurology Research Inc.) Toronto Ontario Canada M3B 2S7
78 Toronto Sunnybrook Hospital Toronto Ontario Canada M4N 3M5
79 The Montreal Neurological Institute Montreal Quebec Canada H3A 2B4
80 McGill Centre for Studies in Aging Verdun Quebec Canada H4H 1R3
81 CHU de Quebec - Hôpital de l' Enfant Jésus Quebec Canada G1J 1Z4
82 CCBR - Ballerup - DK Ballerup Denmark 2750
83 Rigshospitalet København Ø Denmark 2100
84 CCBR - Vejle - DK Vejle Denmark 7100
85 CCBR - Ålborg - DK Ålborg Denmark 9100
86 CHU Strasbourg - Hôpital Hautepierre Strasbourg Cedex Bas Rhin France 67098
87 Hopital Louis Pasteur Colmar Strasbourg Bas Rhin France 67091
88 Groupe Hospitalier Pellegrin - Hôpital Pellegrin Bordeaux Gironde France 33076
89 CHU Reims - Hôpital Maison Blanche Reims Marne France 51092
90 Hopital Neurologique Pierre Wertheimer Bron Cedex Rhone France 69677
91 Groupe hospitalier Broca - La Rochefoucauld - La Collégiale Paris France 75013
92 Groupe Hospitalier Pitie-Salpetriere Paris France 75013
93 Praxis Dr. Scholz Boeblingen Baden Wuerttemberg Germany 71034
94 Aerztliche Gemeinschaftspraxis Ostfildern Baden Wuerttemberg Germany 73760
95 Neuro MVZ Stuttgart Stuttgart Baden Wuerttemberg Germany 70182
96 Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt Bayern Germany 97080
97 Praxis Dr. med. Bergmann Neuburg Bayern Germany 86633
98 Neurologische Gemeinschaftspraxis Kassel Kassel Hessen Germany 34121
99 Klinische Forschung Hannover-Mitte GmbH Hannover Niedersachsen Germany 30159
100 Universitaetsklinikum Aachen AOeR Aachen Nordrhein Westfalen Germany 52074
101 Universitaetsklinikum Bonn AoeR Bonn Nordrhein Westfalen Germany 53127
102 Universitaetsklinikum Koeln Cologne Nordrhein Westfalen Germany 53105
103 Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin Berlin Germany 14050
104 Azienda Ospedaliero Universitaria Ospedali Riuniti Torrette Di Ancona Ancona Italy 60126
105 Fondazione Istituto G.Giglio di Cefalù Cefalù Palermo Italy 90015
106 Azienda Ospedaliera Ospedali Riuniti di Bergamo Bergamo Italy 24100
107 Azienda Ospedaliera Spedali Civili di Brescia Brescia Italy 25100
108 Azienda Ospedaliero Universitaria San Martino Genova Italy 16132
109 Ospedale San Raffaele Milano Italy 20132
110 Casa di Cura del Policlinico Milano Italy 20144
111 Azienda Ospedaliera Universitaria "Federico II" Napoli Italy 80131
112 Seconda Università degli Studi di Napoli Napoli Italy 80138
113 Azienda Ospedaliero Universitaria Pisana Pisa Italy 56126
114 Policlinico Universitario Agostino Gemelli Roma Italy 00168
115 Azienda Ospedaliera Universitaria OO. RR. S. Giovanni di Dio e Ruggi D'Aragona Salerno Italy 84131
116 A.O.U. Senese Policlinico Santa Maria alle Scotte Siena Italy 53100
117 Research Site Chiba-Shi Chiba-Ken Japan 263-0043
118 Research Site Inzai-shi Chiba-Ken Japan
119 Research Site Kurume-shi Fukuoka-ken Japan 830-0011
120 Research Site Aizuwakamatsu-shi Fukushima-Ken Japan 965-8585
121 Research Site Asahikawa-shi Hokkaido Japan 070-8644
122 Research Site Sapporo-shi Hokkaido Japan 006-8555
123 Research Site Sapporo-shi Hokkaido Japan 064-8570
124 Research Site Atsugi-shi Kanagawa-Ken Japan 243-8551
125 Research Site Kamakura-shi Kanagawa-Ken Japan 247-8533
126 Research Site Kawasaki-Shi Kanagawa-Ken Japan 211-8533
127 Yokohama-shi Kanagawa-ken Japan 223-0059
128 Research Site Yokohama-shi Kanagawa-Ken Japan 225-0013
129 Research Site Yokohama-shi Kanagawa-Ken Japan 225-0025
130 Research Site Kyoto-shi Kyoto-Fu Japan 616-8255
131 Research Site Nagaoka-shi Niigata-Ken Japan 940-2081
132 Research Site Iruma-gun Saitama-Ken Japan 350-0495
133 Research Site Kasukabe-shi Saitama-Ken Japan 344-0036
134 Research Site Bunkyo-ku Tokyo-To Japan 113-0034
135 Research Site Shinjuku-ku (I) Tokyo-To Japan 162-8655
136 Research Site Shinjuku-ku Tokyo-To Japan 162-8655
137 Research Site Ota-ku Tokyo Japan 143-8541
138 Research Site Yamagata-shi Yamagata-Ken Japan 990-0834
139 Research Site Itabashi-ku Japan 173-0015
140 Research Site Itabashi-ku Japan 173-8610
141 Research Site Kiyose-shi Japan
142 Research Site Kodaira-shi Japan 187-8551
143 Inha University Hospital Incheon Gyeonggi-do Korea, Republic of 22332
144 Seoul National University Bundang Hospital Seongnam-si Gyeonggi-do Korea, Republic of 13620
145 Gachon University Gil Medical Center Incheon Korea, Republic of 21565
146 Asan Medical Center Seoul Korea, Republic of 05505
147 Samsung Medical Center Seoul Korea, Republic of 06351
148 Konkuk University Medical Center Seoul Korea, Republic of 143-729
149 Hospital Professor Doutor Fernando Fonseca, E.P.E. Amadora Portugal 2720-276
150 Hospital de Braga Braga Portugal 4710-243
151 Centro Hospitalar e Universitário de Coimbra E.P.E Coimbra Portugal 3040-278
152 CUF Alvalade Lisboa Portugal 1600-618
153 Hospital Beatriz Ângelo Loures Portugal 2674-514
154 Campus Neurologico Senior Torres Vedras Portugal 2560-280
155 Policlinica Guipuzcoa San Sebastian Guipuzcoa Spain 20014
156 Hospital de Cruces Barakaldo Vizcaya Spain 48903
157 Fundacio ACE Barcelona Spain 08028
158 Hospital Clinic i Provincial de Barcelona Barcelona Spain 08036
159 Hospital de la Santa Creu i Sant Pau Barcelona Spain 08041
160 Clinica Ruber Madrid Spain 28006
161 Hospital Universitario Dr. Peset Valencia Spain 46017
162 Hospital Universitari i Politecnic La Fe Valencia Spain 46026
163 Changhua Christian Hospital Changhua Taiwan 500
164 Kaohsiung Medical University Chung-Ho Memorial Hospital Kaohsiung Taiwan 807
165 Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan 83301
166 National Cheng Kung University Hospital Tainan Taiwan 704
167 National Taiwan University Hospital Taipei Taiwan 100
168 Chang Gung Memorial Hospital, Linkou Taoyuan County Taiwan 333
169 Southmead Hospital Bristol Avon United Kingdom BS16 1LE
170 Re:Cognition Health Ltd London Greater London United Kingdom W1G 9JF
171 Charing Cross Hospital London Greater London United Kingdom W6 8RF
172 The National Hospital for Neurology and Neurosurgery Centre London Greater London United Kingdom WC1N 3BG
173 Salford Royal Salford Greater Manchester United Kingdom M6 8HD
174 The University of Edinburgh Edinburgh Lothian Region United Kingdom EH8 9YL
175 Manchester Royal Infirmary Blackburn Merseyside United Kingdom BB3 2HH
176 The RICE Centre Bath Somerset United Kingdom BA1 3NG
177 Glasgow Memory Clinic Ltd Glasgow Strathclyde United Kingdom G20 0XA
178 Stobhill ACH Hospital Glasgow Strathclyde United Kingdom G21 3UW
179 Ninewells Hospital Dundee Tayside Region United Kingdom DD2 1GZ
180 Newcastle University Newcastle upon Tyne Tyne & Wear United Kingdom NE4 5PL
181 Kingshill Research Centre Chippenham Wiltshire United Kingdom SN15 1GG

Sponsors and Collaborators

  • Biogen

Investigators

  • Study Director: Medical Director, Biogen

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT02477800
Other Study ID Numbers:
  • 221AD301
  • 2015-000966-72
First Posted:
Jun 23, 2015
Last Update Posted:
Sep 2, 2021
Last Verified:
Aug 1, 2021
Keywords provided by Biogen
BIIB037
Aducanumab
Additional relevant MeSH terms:
Alzheimer Disease

Study Results

Participant Flow

Recruitment Details Participants were enrolled at 169 investigational sites in Australia, Austria, Canada, Denmark, France, Germany, Italy, Japan, Portugal, Republic of Korea, Spain, Taiwan, the United Kingdom (UK) and the United States (US) from 13 August, 2015 to 04 July, 2018.
Pre-assignment Detail A total of 1653 participants with Alzheimer's disease were enrolled and randomized in the study. Of these, 1647 participants received the study drug in placebo-controlled (PC) period. After completing PC period, 852 participants entered and dosed in long-term extension (LTE) period and no participants completed the study due to early termination of the study.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) BIIB037 Late Start: Low Dose (LTE Period) BIIB037 Late Start: High Dose (LTE Period) BIIB037 Early Start: Low Dose (LTE Period) BIIB037 Early Start: High Dose (LTE Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Following PC period, participants randomized to placebo received BIIB037 low dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to placebo received BIIB037 high dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to low dose BIIB037 continued to receive the same dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to high dose BIIB037 continued to receive the same dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period.
Period Title: Placebo-Controlled Period
STARTED 545 547 555 0 0 0 0
COMPLETED 325 325 288 0 0 0 0
NOT COMPLETED 220 222 267 0 0 0 0
Period Title: Placebo-Controlled Period
STARTED 0 0 0 150 152 299 251
COMPLETED 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 150 152 299 251

Baseline Characteristics

Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) Total
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Total of all reporting groups
Overall Participants 545 547 555 1647
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
69.8
(7.72)
70.4
(6.96)
70.0
(7.65)
70.1
(7.45)
Sex: Female, Male (Count of Participants)
Female
287
52.7%
284
51.9%
292
52.6%
863
52.4%
Male
258
47.3%
263
48.1%
263
47.4%
784
47.6%
Race/Ethnicity, Customized (Count of Participants)
Asian
55
10.1%
55
10.1%
65
11.7%
175
10.6%
Black or African American
5
0.9%
1
0.2%
2
0.4%
8
0.5%
Native Hawaiian or other Pacific Islander
0
0%
1
0.2%
0
0%
1
0.1%
White
413
75.8%
412
75.3%
413
74.4%
1238
75.2%
Not Reported due to Confidentiality Regulations
69
12.7%
74
13.5%
72
13%
215
13.1%
Other
3
0.6%
4
0.7%
3
0.5%
10
0.6%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino
13
2.4%
11
2%
13
2.3%
37
2.2%
Not Hispanic or Latino
489
89.7%
492
89.9%
499
89.9%
1480
89.9%
Not Reported due to Confidentiality Regulations
43
7.9%
44
8%
43
7.7%
130
7.9%

Outcome Measures

1. Primary Outcome
Title Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 78
Description CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic patient examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. Prespecified severity anchors range from none = 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). "Sum of boxes" scoring methodology sums the score for each of the 6 domains and provides a value ranging from 0 to 18 that can change in increments of 0.5 or greater. Higher scores indicate greater disease severity. Mixed model for repeated measures (MMRM) analysis was used to analyze change from baseline in CDR-SB. A positive change from baseline indicates clinical decline.
Time Frame Baseline, Week 78

Outcome Measure Data

Analysis Population Description
ITT was defined as all randomized participants who had received at least one dose of study treatment (Aducanumab or Placebo). 'Number of Participants Analyzed' signifies number of participants analyzed in this outcome measure.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years.
Measure Participants 333 331 295
Mean (Standard Error) [score on a scale]
1.56
(0.108)
1.38
(0.108)
1.59
(0.111)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 Low Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in CDR-SB as dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline CDR-SB, baseline CDR-SB by visit interaction, baseline MMSE, AD symptomatic medication use at baseline, region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.2250
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.110
Confidence Interval (2-Sided) 95%
-0.469 to 0.403
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 High Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in CDR-SB as dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline CDR-SB, baseline CDR-SB by visit interaction, baseline MMSE, AD symptomatic medication use at baseline, region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.8330
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from late start group
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.262 to 0.326
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Change From Baseline in Mini-Mental State Examination (MMSE) Score at Week 78
Description The MMSE is a widely used performance-based test of global cognitive status. It consists of 11 tasks that assess orientation, word recall, attention and calculation, language abilities, and visuospatial functions. The scores from the 11 tests are combined to obtain the total score, which ranges from 0 to 30, with lower scores over time indicating increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in MMSE. A negative change from baseline indicates clinical decline.
Time Frame Baseline, Week 78

Outcome Measure Data

Analysis Population Description
ITT was defined as all randomized participants who had received at least one dose of study treatment (Aducanumab or Placebo). 'Number of Participants Analyzed' signifies number of participants analyzed in this outcome measure.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years.
Measure Participants 332 334 297
Mean (Standard Error) [score on a scale]
-3.5
(0.21)
-3.3
(0.21)
-3.6
(0.21)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 Low Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference from Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MMSE as dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline MMSE, baseline MMSE by visit interaction, AD symptomatic medication use at baseline, region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4795
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-0.35 to 0.74
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 High Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference from Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MMSE as dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline MMSE, baseline MMSE by visit interaction, AD symptomatic medication use at baseline, region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.8106
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.62 to 0.49
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) Score at Week 78
Description ADAS-Cog13 comprises both cognitive tasks and clinical ratings of cognitive performance. The scale items capture word recall, ability to follow commands, the ability to correctly copy or draw an image, naming, the ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure for delayed word recall and concentration/distractibility. The total score ranges from 0 to 85. An increase in score over time indicates increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in ADAS-Cog 13. A positive change from baseline indicates clinical decline.
Time Frame Baseline, Week 78

Outcome Measure Data

Analysis Population Description
ITT was defined as all randomized participants who had received at least one dose of study treatment (Aducanumab or Placebo). 'Number of Participants Analyzed' signifies number of participants analyzed in this outcome measure.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years.
Measure Participants 331 332 294
Mean (Standard Error) [score on a scale]
5.140
(0.3783)
4.558
(0.3780)
4.552
(0.3872)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 Low Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo,BIIB037 Low Dose,BIIB037 High Dose),difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in ADAS-Cog 13 as dependent variable and with fixed effects of treatment group,categorical visit,treatment-by-visit interaction,baseline ADAS-Cog 13,baseline ADAS-Cog 13 by visit interaction,baseline MMSE,AD symptomatic medication use at baseline,region,and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.2536
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.583
Confidence Interval (2-Sided) 95%
-1.5835 to 0.4181
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 High Dose (PC Period)
Comments Adjusted mean for each treatment group (Placebo,BIIB037 Low Dose,BIIB037 High Dose),difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in ADAS-Cog 13 as dependent variable and with fixed effects of treatment group,categorical visit,treatment-by-visit interaction,baseline ADAS-Cog 13,baseline ADAS-Cog 13 by visit interaction,baseline MMSE,AD symptomatic medication use at baseline,region,and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.2578
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.588
Confidence Interval (2-Sided) 95%
-1.6067 to 0.4309
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL-MCI) Score at Week 78
Description The ADCS-ADL-MCI consists of 17 instrumental items (e.g., shopping, preparing meals, using household appliances) and 1 basic item (getting dressed). Ratings reflect caregiver observations about the patient's actual functioning over the previous month and provide an assessment of change in the functional state of the participant over time. The total score ranges from 0 to 53, with lower values over time reflecting functional deterioration. MMRM analysis was used to analyze change from baseline in ADAS-ADL-MCI. A negative change from baseline indicates clinical decline.
Time Frame Baseline, Week 78

Outcome Measure Data

Analysis Population Description
ITT was defined as all randomized participants who had received at least one dose of study treatment (Aducanumab or Placebo). 'Number of Participants Analyzed' signifies number of participants analyzed in this outcome measure.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years.
Measure Participants 331 330 298
Mean (Standard Error) [score on a scale]
-3.8
(0.35)
-3.1
(0.35)
-3.1
(0.35)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 Low Dose (PC Period)
Comments Adjusted mean for each group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference with Placebo,95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in ADCS-ADL-MCI as dependent variable and with fixed effects of treatment group,categorical visit,treatment-by-visit interaction, baseline ADCS-ADL-MCI, baseline ADCS-ADL-MCI by visit interaction, baseline MMSE AD symptomatic medication use at baseline,region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.1225
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.19 to 1.64
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo (PC Period), BIIB037 High Dose (PC Period)
Comments Adjusted mean for each group (Placebo, BIIB037 Low Dose, BIIB037 High Dose), difference with Placebo,95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in ADCS-ADL-MCI as dependent variable and with fixed effects of treatment group,categorical visit,treatment-by-visit interaction, baseline ADCS-ADL-MCI, baseline ADCS-ADL-MCI by visit interaction, baseline MMSE AD symptomatic medication use at baseline,region, and laboratory ApoE status.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.1506
Comments
Method MMRM Model
Comments
Method of Estimation Estimation Parameter Difference from late start group
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.25 to 1.61
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time Frame From First Dose to End of Study (up to 4 years)
Adverse Event Reporting Description Safety population was all randomized participants who received at least one dose of study treatment. In PC period, 5 participants randomized to placebo, inadvertently received 1 or more doses of active treatment during the PC period. For participants affected, a participant was counted only once within each system organ class/preferred term/study period.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) BIIB037 Late Start: Low Dose (LTE Period) BIIB037 Late Start: High Dose (LTE Period) BIIB037 Early Start: Low Dose (LTE Period) BIIB037 Early Start: High Dose (LTE Period)
Arm/Group Description Participants received a maximum of 20 infusions of BIIB037-matching placebo intravenously (IV) in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 low dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Participants received a maximum of 20 infusions of BIIB037 high dose IV in PC period, administered approximately once every 4 weeks for up to approximately 1.5 years. Following PC period, participants randomized to placebo received BIIB037 low dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to placebo received BIIB037 high dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to low dose BIIB037 continued to receive the same dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period. Following PC period, participants randomized to high dose BIIB037 continued to receive the same dose, IV infusion, approximately every 4 weeks for up to 2 years in LTE period.
All Cause Mortality
Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) BIIB037 Late Start: Low Dose (LTE Period) BIIB037 Late Start: High Dose (LTE Period) BIIB037 Early Start: Low Dose (LTE Period) BIIB037 Early Start: High Dose (LTE Period)
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 0/540 (0%) 3/549 (0.5%) 2/558 (0.4%) 1/150 (0.7%) 1/152 (0.7%) 1/299 (0.3%) 2/251 (0.8%)
Serious Adverse Events
Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) BIIB037 Late Start: Low Dose (LTE Period) BIIB037 Late Start: High Dose (LTE Period) BIIB037 Early Start: Low Dose (LTE Period) BIIB037 Early Start: High Dose (LTE Period)
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 70/540 (13%) 76/549 (13.8%) 79/558 (14.2%) 19/150 (12.7%) 14/152 (9.2%) 35/299 (11.7%) 25/251 (10%)
Blood and lymphatic system disorders
Blood loss anaemia 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Leukocytosis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Cardiac disorders
Acute myocardial infarction 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 1/150 (0.7%) 1/152 (0.7%) 2/299 (0.7%) 0/251 (0%)
Angina pectoris 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Arrhythmia 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Atrial fibrillation 6/540 (1.1%) 4/549 (0.7%) 3/558 (0.5%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 1/251 (0.4%)
Atrial flutter 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Atrioventricular block 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Atrioventricular block complete 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Bradycardia 1/540 (0.2%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Bundle branch block right 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cardiac arrest 0/540 (0%) 1/549 (0.2%) 2/558 (0.4%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cardiac failure 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cardiac failure congestive 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Coronary artery disease 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Coronary artery occlusion 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Coronary artery stenosis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Mitral valve incompetence 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Myocardial infarction 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 1/152 (0.7%) 1/299 (0.3%) 0/251 (0%)
Myocardial ischaemia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Sinus bradycardia 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Sinus node dysfunction 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Supraventricular tachycardia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Tachycardia 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Congenital, familial and genetic disorders
Encephalocele 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hypertrophic cardiomyopathy 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ear and labyrinth disorders
Labyrinthine fistula 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Eye disorders
Cataract 2/540 (0.4%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Diplopia 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Retinal artery occlusion 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastrointestinal disorders
Abdominal distension 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Abdominal pain 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Abdominal pain lower 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Constipation 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Diverticulum intestinal 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Duodenal ulcer 1/540 (0.2%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Enteritis 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastric ulcer haemorrhage 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastritis 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Gastrointestinal haemorrhage 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastrooesophageal reflux disease 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Haemorrhoids 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hiatus hernia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ileus 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Inguinal hernia 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 2/251 (0.8%)
Intestinal obstruction 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Intestinal perforation 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Large intestinal ulcer 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Large intestine perforation 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Large intestine polyp 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Mallory-weiss syndrome 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Melaena 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Obstructive pancreatitis 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Oesophageal ulcer 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Pancreatic disorder 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Pancreatitis acute 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Small intestinal obstruction 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Upper gastrointestinal haemorrhage 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
General disorders
Asthenia 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Chest pain 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 2/150 (1.3%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Fatigue 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Gait disturbance 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
General physical health deterioration 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Incarcerated hernia 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Non-cardiac chest pain 3/540 (0.6%) 1/549 (0.2%) 2/558 (0.4%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 1/251 (0.4%)
Hepatobiliary disorders
Bile duct stone 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cholangitis acute 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cholecystitis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cholecystitis acute 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cholelithiasis 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Infections and infestations
Appendicitis 1/540 (0.2%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Appendicitis perforated 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Arthritis bacterial 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Arthritis infective 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Bronchitis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Candida infection 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cellulitis 2/540 (0.4%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Cholecystitis infective 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Diverticulitis 0/540 (0%) 0/549 (0%) 2/558 (0.4%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Escherichia urinary tract infection 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastroenteritis 0/540 (0%) 0/549 (0%) 2/558 (0.4%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Infection 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Influenza 2/540 (0.4%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Paronychia 1/540 (0.2%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Pneumonia 2/540 (0.4%) 1/549 (0.2%) 4/558 (0.7%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 1/251 (0.4%)
Pneumonia pneumococcal 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Post procedural infection 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Post procedural sepsis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Postoperative wound infection 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Respiratory tract infection 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Sepsis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Serratia infection 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Staphylococcal infection 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Subcutaneous abscess 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Urinary tract infection 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Urosepsis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Wound infection staphylococcal 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture 2/540 (0.4%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Compression fracture 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Concussion 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Craniocerebral injury 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Exposure to toxic agent 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Extradural haematoma 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Facial bones fracture 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Fall 6/540 (1.1%) 12/549 (2.2%) 4/558 (0.7%) 4/150 (2.7%) 0/152 (0%) 7/299 (2.3%) 2/251 (0.8%)
Femoral neck fracture 2/540 (0.4%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Femur fracture 1/540 (0.2%) 2/549 (0.4%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Fibula fracture 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Foot fracture 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Forearm fracture 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hand fracture 2/540 (0.4%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Heat illness 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Humerus fracture 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 2/299 (0.7%) 0/251 (0%)
Jaw fracture 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Joint dislocation 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ligament injury 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Limb crushing injury 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Lower limb fracture 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Lumbar vertebral fracture 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Meniscus injury 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Overdose 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Post procedural complication 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Postoperative respiratory failure 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Radius fracture 0/540 (0%) 2/549 (0.4%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Rib fracture 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Road traffic accident 2/540 (0.4%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Scapula fracture 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Skull fracture 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Spinal compression fracture 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Spinal fracture 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Subdural haematoma 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Subdural haemorrhage 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Thermal burn 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Tibia fracture 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Tooth fracture 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ulna fracture 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Upper limb fracture 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Wrist fracture 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Investigations
Blood ketone body increased 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Blood pressure increased 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Metabolism and nutrition disorders
Decreased appetite 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Dehydration 2/540 (0.4%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Gout 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hypoglycaemia 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hypokalaemia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hyponatraemia 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 1/299 (0.3%) 0/251 (0%)
Musculoskeletal and connective tissue disorders
Bone pain 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Intervertebral disc compression 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Intervertebral disc protrusion 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Muscular weakness 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Osteoarthritis 0/540 (0%) 2/549 (0.4%) 2/558 (0.4%) 0/150 (0%) 0/152 (0%) 2/299 (0.7%) 1/251 (0.4%)
Osteonecrosis 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Rotator cuff syndrome 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Spondylolisthesis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Vertebral foraminal stenosis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Vertebral osteophyte 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Adenocarcinoma of colon 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Basal cell carcinoma 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Breast cancer 1/540 (0.2%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Breast cancer stage i 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Colon cancer 1/540 (0.2%) 1/549 (0.2%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Gastric cancer 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Invasive papillary breast carcinoma 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Lung adenocarcinoma 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Lung neoplasm malignant 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Lymphoma 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Malignant melanoma 2/540 (0.4%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Mesothelioma 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Metastases to liver 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Metastases to peritoneum 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Myeloproliferative neoplasm 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Neurofibrosarcoma 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Non-small cell lung cancer 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Oesophageal adenocarcinoma 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ovarian cancer stage iii 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Pancreatic carcinoma 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 1/299 (0.3%) 0/251 (0%)
Pancreatic carcinoma metastatic 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Polycythaemia vera 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Prostate cancer 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Prostate cancer stage 0 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Transitional cell carcinoma 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Tubular breast carcinoma 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Nervous system disorders
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits 0/540 (0%) 0/549 (0%) 2/558 (0.4%) 1/150 (0.7%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Amyloid related imaging abnormality-oedema/effusion 0/540 (0%) 2/549 (0.4%) 7/558 (1.3%) 2/150 (1.3%) 2/152 (1.3%) 0/299 (0%) 0/251 (0%)
Balance disorder 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Carotid artery stenosis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cerebral haematoma 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cerebral haemorrhage 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cerebral infarction 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Cerebral ischaemia 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Cerebrovascular accident 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Dementia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Dementia alzheimer's type 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 1/251 (0.4%)
Dementia with lewy bodies 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Dysarthria 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Dystonia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Focal dyscognitive seizures 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Generalised tonic-clonic seizure 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Haemorrhage intracranial 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Head discomfort 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Headache 1/540 (0.2%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 2/251 (0.8%)
Hypoaesthesia 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Ischaemic stroke 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Lacunar infarction 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Lacunar stroke 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Loss of consciousness 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Migraine 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Myasthenia gravis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Myelitis transverse 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Myoclonus 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Nervous system disorder 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Orthostatic intolerance 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Parkinson's disease 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Partial seizures 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Peroneal nerve palsy 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Presyncope 0/540 (0%) 1/549 (0.2%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Seizure 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Subarachnoid haemorrhage 2/540 (0.4%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Superficial siderosis of central nervous system 0/540 (0%) 0/549 (0%) 2/558 (0.4%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Syncope 2/540 (0.4%) 4/549 (0.7%) 5/558 (0.9%) 1/150 (0.7%) 1/152 (0.7%) 2/299 (0.7%) 0/251 (0%)
Transient ischaemic attack 1/540 (0.2%) 2/549 (0.4%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Vertebral artery dissection 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Psychiatric disorders
Agitation 1/540 (0.2%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Anxiety 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Completed suicide 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Delirium 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 1/251 (0.4%)
Depression 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Generalised anxiety disorder 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Mental status changes 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Persistent depressive disorder 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Psychogenic tremor 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Psychotic disorder 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Suicide attempt 0/540 (0%) 2/549 (0.4%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Renal and urinary disorders
Acute kidney injury 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Nephrolithiasis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Renal colic 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Ureterolithiasis 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Urinary retention 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Prostatic dysplasia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Asthmatic crisis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Chronic obstructive pulmonary disease 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Nasal obstruction 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Organising pneumonia 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Pleural effusion 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 1/152 (0.7%) 0/299 (0%) 0/251 (0%)
Pneumonia aspiration 0/540 (0%) 0/549 (0%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Pneumothorax 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 2/299 (0.7%) 1/251 (0.4%)
Pulmonary embolism 2/540 (0.4%) 1/549 (0.2%) 3/558 (0.5%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 1/251 (0.4%)
Pulmonary infarction 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Respiratory failure 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Skin and subcutaneous tissue disorders
Angioedema 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Urticaria 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Vascular disorders
Aortic aneurysm 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Aortic dissection 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Aortic stenosis 1/540 (0.2%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Deep vein thrombosis 1/540 (0.2%) 1/549 (0.2%) 4/558 (0.7%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hypertension 1/540 (0.2%) 1/549 (0.2%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Hypertensive emergency 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Hypotension 0/540 (0%) 1/549 (0.2%) 0/558 (0%) 1/150 (0.7%) 0/152 (0%) 0/299 (0%) 1/251 (0.4%)
Orthostatic hypotension 0/540 (0%) 0/549 (0%) 0/558 (0%) 0/150 (0%) 0/152 (0%) 1/299 (0.3%) 0/251 (0%)
Peripheral arterial occlusive disease 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Peripheral artery stenosis 0/540 (0%) 0/549 (0%) 1/558 (0.2%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Other (Not Including Serious) Adverse Events
Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) BIIB037 Late Start: Low Dose (LTE Period) BIIB037 Late Start: High Dose (LTE Period) BIIB037 Early Start: Low Dose (LTE Period) BIIB037 Early Start: High Dose (LTE Period)
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 327/540 (60.6%) 396/549 (72.1%) 410/558 (73.5%) 89/150 (59.3%) 90/152 (59.2%) 130/299 (43.5%) 121/251 (48.2%)
Gastrointestinal disorders
Diarrhoea 44/540 (8.1%) 49/549 (8.9%) 52/558 (9.3%) 6/150 (4%) 8/152 (5.3%) 16/299 (5.4%) 9/251 (3.6%)
Nausea 42/540 (7.8%) 30/549 (5.5%) 40/558 (7.2%) 5/150 (3.3%) 10/152 (6.6%) 13/299 (4.3%) 6/251 (2.4%)
General disorders
Fatigue 38/540 (7%) 30/549 (5.5%) 34/558 (6.1%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Infections and infestations
Nasopharyngitis 64/540 (11.9%) 65/549 (11.8%) 68/558 (12.2%) 11/150 (7.3%) 11/152 (7.2%) 20/299 (6.7%) 15/251 (6%)
Upper respiratory tract infection 49/540 (9.1%) 47/549 (8.6%) 51/558 (9.1%) 10/150 (6.7%) 12/152 (7.9%) 21/299 (7%) 20/251 (8%)
Urinary tract infection 37/540 (6.9%) 30/549 (5.5%) 34/558 (6.1%) 12/150 (8%) 5/152 (3.3%) 16/299 (5.4%) 14/251 (5.6%)
Injury, poisoning and procedural complications
Contusion 23/540 (4.3%) 33/549 (6%) 36/558 (6.5%) 4/150 (2.7%) 6/152 (3.9%) 17/299 (5.7%) 4/251 (1.6%)
Fall 54/540 (10%) 70/549 (12.8%) 83/558 (14.9%) 11/150 (7.3%) 18/152 (11.8%) 28/299 (9.4%) 22/251 (8.8%)
Musculoskeletal and connective tissue disorders
Arthralgia 28/540 (5.2%) 27/549 (4.9%) 35/558 (6.3%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Back pain 42/540 (7.8%) 26/549 (4.7%) 44/558 (7.9%) 0/150 (0%) 0/152 (0%) 0/299 (0%) 0/251 (0%)
Nervous system disorders
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits 34/540 (6.3%) 89/549 (16.2%) 102/558 (18.3%) 23/150 (15.3%) 22/152 (14.5%) 16/299 (5.4%) 18/251 (7.2%)
Amyloid related imaging abnormality-oedema/effusion 16/540 (3%) 140/549 (25.5%) 195/558 (34.9%) 33/150 (22%) 43/152 (28.3%) 19/299 (6.4%) 21/251 (8.4%)
Dizziness 54/540 (10%) 49/549 (8.9%) 54/558 (9.7%) 6/150 (4%) 4/152 (2.6%) 14/299 (4.7%) 13/251 (5.2%)
Headache 81/540 (15%) 98/549 (17.9%) 115/558 (20.6%) 14/150 (9.3%) 19/152 (12.5%) 27/299 (9%) 24/251 (9.6%)
Superficial siderosis of central nervous system 10/540 (1.9%) 51/549 (9.3%) 88/558 (15.8%) 15/150 (10%) 17/152 (11.2%) 9/299 (3%) 14/251 (5.6%)
Psychiatric disorders
Anxiety 28/540 (5.2%) 32/549 (5.8%) 28/558 (5%) 7/150 (4.7%) 4/152 (2.6%) 12/299 (4%) 14/251 (5.6%)
Depression 34/540 (6.3%) 40/549 (7.3%) 34/558 (6.1%) 8/150 (5.3%) 5/152 (3.3%) 9/299 (3%) 9/251 (3.6%)
Confusional state 0/540 (0%) 0/549 (0%) 0/558 (0%) 5/150 (3.3%) 9/152 (5.9%) 4/299 (1.3%) 3/251 (1.2%)
Respiratory, thoracic and mediastinal disorders
Cough 33/540 (6.1%) 29/549 (5.3%) 19/558 (3.4%) 9/150 (6%) 4/152 (2.6%) 12/299 (4%) 6/251 (2.4%)

Limitations/Caveats

The study was halted prematurely based on a prespecified futility analysis and not based on safety concerns. Participants discontinued due to study termination are included in "Reason not Specified" category in participant flow tables above.

More Information

Certain Agreements

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

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.

Results Point of Contact

Name/Title Biogen Study Medical Director
Organization Biogen
Phone 866-633-4636
Email clinicaltrials@biogen.com
Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT02477800
Other Study ID Numbers:
  • 221AD301
  • 2015-000966-72
First Posted:
Jun 23, 2015
Last Update Posted:
Sep 2, 2021
Last Verified:
Aug 1, 2021