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Trial record 8 of 9 for:    aducanumab

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

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: NCT02477800
Recruitment Status : Terminated (Study was discontinued based on futility analysis done and not based on safety concerns. Follow-up visits and closing out study activities are completed)
First Posted : June 23, 2015
Results First Posted : September 2, 2021
Last Update Posted : September 2, 2021
Sponsor:
Information provided by (Responsible Party):
Biogen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Alzheimer's Disease
Interventions Drug: Aducanumab (BIIB037)
Drug: Placebo
Enrollment 1653
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 Details 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)
Hide 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
Reason Not Completed
Adverse Event             16             25             28             0             0             0             0
Change of Treatment             1             2             1             0             0             0             0
Consent Withdrawn             26             16             27             0             0             0             0
Death             0             3             2             0             0             0             0
Disease Progression             1             0             1             0             0             0             0
Investigator Decision             3             2             1             0             0             0             0
Lost to Follow-up             1             3             3             0             0             0             0
Relocation             2             0             0             0             0             0             0
Site Terminated by Investigator             1             1             1             0             0             0             0
Site Terminated by Sponsor             2             1             0             0             0             0             0
Study Visit Burden             5             3             11             0             0             0             0
Withdrawal by Parent/Guardian             1             5             3             0             0             0             0
Reason not Specified             161             161             189             0             0             0             0
Period Title: Long Term Extension Period
Started 0 0 0 150 [1] 152 [2] 299 [3] 251 [4]
Completed 0 0 0 0 0 0 0
Not Completed 0 0 0 150 152 299 251
Reason Not Completed
Adverse Event             0             0             0             6             2             4             3
Death             0             0             0             1             1             1             2
Consent Withdrawn             0             0             0             10             4             13             16
Disease Progression             0             0             0             3             1             1             0
Investigator Decision             0             0             0             0             0             0             2
Lost to Follow-up             0             0             0             0             1             3             0
Site Terminated By Sponsor             0             0             0             0             0             2             1
Study Visit Burden             0             0             0             3             0             2             2
Withdrawal by Parent/Guardian             0             0             0             1             3             3             1
Reason not Specified             0             0             0             126             140             270             224
[1]
12 PC completers did not enter LTE.
[2]
11 PC completers did not enter LTE.
[3]
26 PC completers did not enter LTE.
[4]
37 PC completers did not enter LTE.
Arm/Group Title Placebo (PC Period) BIIB037 Low Dose (PC Period) BIIB037 High Dose (PC Period) Total
Hide 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 Number of Baseline Participants 545 547 555 1647
Hide Baseline Analysis Population Description
The Intent to Treat (ITT) population was defined as all randomized participants who received at least 1 dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 545 participants 547 participants 555 participants 1647 participants
69.8  (7.72) 70.4  (6.96) 70.0  (7.65) 70.1  (7.45)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 545 participants 547 participants 555 participants 1647 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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 545 participants 547 participants 555 participants 1647 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
   0.0%
1
   0.2%
0
   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
  13.0%
215
  13.1%
Other
3
   0.6%
4
   0.7%
3
   0.5%
10
   0.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 545 participants 547 participants 555 participants 1647 participants
Hispanic or Latino
13
   2.4%
11
   2.0%
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
   8.0%
43
   7.7%
130
   7.9%
1.Primary Outcome
Title Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 78
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 333 331 295
Mean (Standard Error)
Unit of Measure: score on a scale
1.56  (0.108) 1.38  (0.108) 1.59  (0.111)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.2250
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.110
Confidence Interval (2-Sided) 95%
-0.469 to 0.403
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.8330
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from late start group
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.262 to 0.326
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Mini-Mental State Examination (MMSE) Score at Week 78
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 332 334 297
Mean (Standard Error)
Unit of Measure: score on a scale
-3.5  (0.21) -3.3  (0.21) -3.6  (0.21)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.4795
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-0.35 to 0.74
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.8106
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.62 to 0.49
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) Score at Week 78
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 331 332 294
Mean (Standard Error)
Unit of Measure: score on a scale
5.140  (0.3783) 4.558  (0.3780) 4.552  (0.3872)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.2536
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.583
Confidence Interval (2-Sided) 95%
-1.5835 to 0.4181
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.2578
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value -0.588
Confidence Interval (2-Sided) 95%
-1.6067 to 0.4309
Estimation Comments [Not Specified]
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 331 330 298
Mean (Standard Error)
Unit of Measure: score on a scale
-3.8  (0.35) -3.1  (0.35) -3.1  (0.35)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.1225
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from Placebo
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.19 to 1.64
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.1506
Comments [Not Specified]
Method MMRM Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference from late start group
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.25 to 1.61
Estimation Comments [Not Specified]
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)
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/540 (0.00%)   3/549 (0.55%)   2/558 (0.36%)   1/150 (0.67%)   1/152 (0.66%)   1/299 (0.33%)   2/251 (0.80%) 
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   70/540 (12.96%)   76/549 (13.84%)   79/558 (14.16%)   19/150 (12.67%)   14/152 (9.21%)   35/299 (11.71%)   25/251 (9.96%) 
Blood and lymphatic system disorders               
Blood loss anaemia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Leukocytosis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Cardiac disorders               
Acute myocardial infarction  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  1/150 (0.67%)  1/152 (0.66%)  2/299 (0.67%)  0/251 (0.00%) 
Angina pectoris  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Arrhythmia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Atrial fibrillation  1  6/540 (1.11%)  4/549 (0.73%)  3/558 (0.54%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  1/251 (0.40%) 
Atrial flutter  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Atrioventricular block  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Atrioventricular block complete  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Bradycardia  1  1/540 (0.19%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Bundle branch block right  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cardiac arrest  1  0/540 (0.00%)  1/549 (0.18%)  2/558 (0.36%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cardiac failure  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cardiac failure congestive  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Coronary artery disease  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Coronary artery occlusion  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Coronary artery stenosis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Mitral valve incompetence  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Myocardial infarction  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  1/152 (0.66%)  1/299 (0.33%)  0/251 (0.00%) 
Myocardial ischaemia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Sinus bradycardia  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Sinus node dysfunction  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Supraventricular tachycardia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Tachycardia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Congenital, familial and genetic disorders               
Encephalocele  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hypertrophic cardiomyopathy  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ear and labyrinth disorders               
Labyrinthine fistula  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Eye disorders               
Cataract  1  2/540 (0.37%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Diplopia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Retinal artery occlusion  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastrointestinal disorders               
Abdominal distension  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Abdominal pain  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Abdominal pain lower  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Constipation  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Diverticulum intestinal  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Duodenal ulcer  1  1/540 (0.19%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Enteritis  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastric ulcer haemorrhage  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastritis  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Gastrointestinal haemorrhage  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastrooesophageal reflux disease  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Haemorrhoids  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hiatus hernia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ileus  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Inguinal hernia  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  2/251 (0.80%) 
Intestinal obstruction  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Intestinal perforation  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Large intestinal ulcer  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Large intestine perforation  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Large intestine polyp  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Mallory-weiss syndrome  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Melaena  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Obstructive pancreatitis  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Oesophageal ulcer  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Pancreatic disorder  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Pancreatitis acute  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Small intestinal obstruction  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Upper gastrointestinal haemorrhage  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
General disorders               
Asthenia  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Chest pain  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  2/150 (1.33%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Fatigue  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Gait disturbance  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
General physical health deterioration  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Incarcerated hernia  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Non-cardiac chest pain  1  3/540 (0.56%)  1/549 (0.18%)  2/558 (0.36%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  1/251 (0.40%) 
Hepatobiliary disorders               
Bile duct stone  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cholangitis acute  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cholecystitis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cholecystitis acute  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cholelithiasis  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Infections and infestations               
Appendicitis  1  1/540 (0.19%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Appendicitis perforated  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Arthritis bacterial  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Arthritis infective  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Bronchitis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Candida infection  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cellulitis  1  2/540 (0.37%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Cholecystitis infective  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Diverticulitis  1  0/540 (0.00%)  0/549 (0.00%)  2/558 (0.36%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Escherichia urinary tract infection  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastroenteritis  1  0/540 (0.00%)  0/549 (0.00%)  2/558 (0.36%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Infection  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Influenza  1  2/540 (0.37%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Paronychia  1  1/540 (0.19%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Pneumonia  1  2/540 (0.37%)  1/549 (0.18%)  4/558 (0.72%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  1/251 (0.40%) 
Pneumonia pneumococcal  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Post procedural infection  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Post procedural sepsis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Postoperative wound infection  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Respiratory tract infection  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Sepsis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Serratia infection  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Staphylococcal infection  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Subcutaneous abscess  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Urinary tract infection  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Urosepsis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Wound infection staphylococcal  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Injury, poisoning and procedural complications               
Cervical vertebral fracture  1  2/540 (0.37%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Compression fracture  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Concussion  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Craniocerebral injury  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Exposure to toxic agent  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Extradural haematoma  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Facial bones fracture  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Fall  1  6/540 (1.11%)  12/549 (2.19%)  4/558 (0.72%)  4/150 (2.67%)  0/152 (0.00%)  7/299 (2.34%)  2/251 (0.80%) 
Femoral neck fracture  1  2/540 (0.37%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Femur fracture  1  1/540 (0.19%)  2/549 (0.36%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Fibula fracture  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Foot fracture  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Forearm fracture  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hand fracture  1  2/540 (0.37%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Heat illness  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Humerus fracture  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  2/299 (0.67%)  0/251 (0.00%) 
Jaw fracture  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Joint dislocation  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ligament injury  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Limb crushing injury  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Lower limb fracture  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Lumbar vertebral fracture  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Meniscus injury  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Overdose  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Post procedural complication  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Postoperative respiratory failure  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Radius fracture  1  0/540 (0.00%)  2/549 (0.36%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Rib fracture  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Road traffic accident  1  2/540 (0.37%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Scapula fracture  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Skull fracture  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Spinal compression fracture  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Spinal fracture  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Subdural haematoma  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Subdural haemorrhage  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Thermal burn  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Tibia fracture  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Tooth fracture  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ulna fracture  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Upper limb fracture  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Wrist fracture  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Investigations               
Blood ketone body increased  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Blood pressure increased  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Metabolism and nutrition disorders               
Decreased appetite  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Dehydration  1  2/540 (0.37%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Gout  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hypoglycaemia  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hypokalaemia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hyponatraemia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  1/299 (0.33%)  0/251 (0.00%) 
Musculoskeletal and connective tissue disorders               
Bone pain  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Intervertebral disc compression  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Intervertebral disc protrusion  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Muscular weakness  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Osteoarthritis  1  0/540 (0.00%)  2/549 (0.36%)  2/558 (0.36%)  0/150 (0.00%)  0/152 (0.00%)  2/299 (0.67%)  1/251 (0.40%) 
Osteonecrosis  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Rotator cuff syndrome  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Spondylolisthesis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Vertebral foraminal stenosis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Vertebral osteophyte  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Acute myeloid leukaemia  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Adenocarcinoma of colon  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Basal cell carcinoma  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Breast cancer  1  1/540 (0.19%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Breast cancer stage i  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Colon cancer  1  1/540 (0.19%)  1/549 (0.18%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Gastric cancer  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Invasive papillary breast carcinoma  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Lung adenocarcinoma  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Lung neoplasm malignant  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Lymphoma  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Malignant melanoma  1  2/540 (0.37%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Mesothelioma  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Metastases to liver  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Metastases to peritoneum  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Myeloproliferative neoplasm  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Neurofibrosarcoma  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Non-small cell lung cancer  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Oesophageal adenocarcinoma  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ovarian cancer stage iii  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Pancreatic carcinoma  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  1/299 (0.33%)  0/251 (0.00%) 
Pancreatic carcinoma metastatic  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Polycythaemia vera  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Prostate cancer  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Prostate cancer stage 0  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Transitional cell carcinoma  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Tubular breast carcinoma  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Nervous system disorders               
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits  1  0/540 (0.00%)  0/549 (0.00%)  2/558 (0.36%)  1/150 (0.67%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Amyloid related imaging abnormality-oedema/effusion  1  0/540 (0.00%)  2/549 (0.36%)  7/558 (1.25%)  2/150 (1.33%)  2/152 (1.32%)  0/299 (0.00%)  0/251 (0.00%) 
Balance disorder  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Carotid artery stenosis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cerebral haematoma  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cerebral haemorrhage  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cerebral infarction  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Cerebral ischaemia  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Cerebrovascular accident  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Dementia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Dementia alzheimer's type  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  1/251 (0.40%) 
Dementia with lewy bodies  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Dysarthria  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Dystonia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Focal dyscognitive seizures  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Generalised tonic-clonic seizure  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Haemorrhage intracranial  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Head discomfort  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Headache  1  1/540 (0.19%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  2/251 (0.80%) 
Hypoaesthesia  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Ischaemic stroke  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Lacunar infarction  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Lacunar stroke  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Loss of consciousness  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Migraine  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Myasthenia gravis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Myelitis transverse  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Myoclonus  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Nervous system disorder  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Orthostatic intolerance  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Parkinson's disease  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Partial seizures  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Peroneal nerve palsy  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Presyncope  1  0/540 (0.00%)  1/549 (0.18%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Seizure  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Subarachnoid haemorrhage  1  2/540 (0.37%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Superficial siderosis of central nervous system  1  0/540 (0.00%)  0/549 (0.00%)  2/558 (0.36%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Syncope  1  2/540 (0.37%)  4/549 (0.73%)  5/558 (0.90%)  1/150 (0.67%)  1/152 (0.66%)  2/299 (0.67%)  0/251 (0.00%) 
Transient ischaemic attack  1  1/540 (0.19%)  2/549 (0.36%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Vertebral artery dissection  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Psychiatric disorders               
Agitation  1  1/540 (0.19%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Anxiety  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Completed suicide  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Delirium  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  1/251 (0.40%) 
Depression  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Generalised anxiety disorder  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Mental status changes  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Persistent depressive disorder  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Psychogenic tremor  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Psychotic disorder  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Suicide attempt  1  0/540 (0.00%)  2/549 (0.36%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Renal and urinary disorders               
Acute kidney injury  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Nephrolithiasis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Renal colic  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Ureterolithiasis  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Urinary retention  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Reproductive system and breast disorders               
Benign prostatic hyperplasia  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Prostatic dysplasia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Acute respiratory failure  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Asthmatic crisis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Chronic obstructive pulmonary disease  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Nasal obstruction  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Organising pneumonia  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Pleural effusion  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  1/152 (0.66%)  0/299 (0.00%)  0/251 (0.00%) 
Pneumonia aspiration  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Pneumothorax  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  2/299 (0.67%)  1/251 (0.40%) 
Pulmonary embolism  1  2/540 (0.37%)  1/549 (0.18%)  3/558 (0.54%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  1/251 (0.40%) 
Pulmonary infarction  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Respiratory failure  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Skin and subcutaneous tissue disorders               
Angioedema  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Urticaria  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Vascular disorders               
Aortic aneurysm  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Aortic dissection  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Aortic stenosis  1  1/540 (0.19%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Deep vein thrombosis  1  1/540 (0.19%)  1/549 (0.18%)  4/558 (0.72%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hypertension  1  1/540 (0.19%)  1/549 (0.18%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Hypertensive emergency  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Hypotension  1  0/540 (0.00%)  1/549 (0.18%)  0/558 (0.00%)  1/150 (0.67%)  0/152 (0.00%)  0/299 (0.00%)  1/251 (0.40%) 
Orthostatic hypotension  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  0/150 (0.00%)  0/152 (0.00%)  1/299 (0.33%)  0/251 (0.00%) 
Peripheral arterial occlusive disease  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Peripheral artery stenosis  1  0/540 (0.00%)  0/549 (0.00%)  1/558 (0.18%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   327/540 (60.56%)   396/549 (72.13%)   410/558 (73.48%)   89/150 (59.33%)   90/152 (59.21%)   130/299 (43.48%)   121/251 (48.21%) 
Gastrointestinal disorders               
Diarrhoea  1  44/540 (8.15%)  49/549 (8.93%)  52/558 (9.32%)  6/150 (4.00%)  8/152 (5.26%)  16/299 (5.35%)  9/251 (3.59%) 
Nausea  1  42/540 (7.78%)  30/549 (5.46%)  40/558 (7.17%)  5/150 (3.33%)  10/152 (6.58%)  13/299 (4.35%)  6/251 (2.39%) 
General disorders               
Fatigue  1  38/540 (7.04%)  30/549 (5.46%)  34/558 (6.09%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Infections and infestations               
Nasopharyngitis  1  64/540 (11.85%)  65/549 (11.84%)  68/558 (12.19%)  11/150 (7.33%)  11/152 (7.24%)  20/299 (6.69%)  15/251 (5.98%) 
Upper respiratory tract infection  1  49/540 (9.07%)  47/549 (8.56%)  51/558 (9.14%)  10/150 (6.67%)  12/152 (7.89%)  21/299 (7.02%)  20/251 (7.97%) 
Urinary tract infection  1  37/540 (6.85%)  30/549 (5.46%)  34/558 (6.09%)  12/150 (8.00%)  5/152 (3.29%)  16/299 (5.35%)  14/251 (5.58%) 
Injury, poisoning and procedural complications               
Contusion  1  23/540 (4.26%)  33/549 (6.01%)  36/558 (6.45%)  4/150 (2.67%)  6/152 (3.95%)  17/299 (5.69%)  4/251 (1.59%) 
Fall  1  54/540 (10.00%)  70/549 (12.75%)  83/558 (14.87%)  11/150 (7.33%)  18/152 (11.84%)  28/299 (9.36%)  22/251 (8.76%) 
Musculoskeletal and connective tissue disorders               
Arthralgia  1  28/540 (5.19%)  27/549 (4.92%)  35/558 (6.27%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Back pain  1  42/540 (7.78%)  26/549 (4.74%)  44/558 (7.89%)  0/150 (0.00%)  0/152 (0.00%)  0/299 (0.00%)  0/251 (0.00%) 
Nervous system disorders               
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits  1  34/540 (6.30%)  89/549 (16.21%)  102/558 (18.28%)  23/150 (15.33%)  22/152 (14.47%)  16/299 (5.35%)  18/251 (7.17%) 
Amyloid related imaging abnormality-oedema/effusion  1  16/540 (2.96%)  140/549 (25.50%)  195/558 (34.95%)  33/150 (22.00%)  43/152 (28.29%)  19/299 (6.35%)  21/251 (8.37%) 
Dizziness  1  54/540 (10.00%)  49/549 (8.93%)  54/558 (9.68%)  6/150 (4.00%)  4/152 (2.63%)  14/299 (4.68%)  13/251 (5.18%) 
Headache  1  81/540 (15.00%)  98/549 (17.85%)  115/558 (20.61%)  14/150 (9.33%)  19/152 (12.50%)  27/299 (9.03%)  24/251 (9.56%) 
Superficial siderosis of central nervous system  1  10/540 (1.85%)  51/549 (9.29%)  88/558 (15.77%)  15/150 (10.00%)  17/152 (11.18%)  9/299 (3.01%)  14/251 (5.58%) 
Psychiatric disorders               
Anxiety  1  28/540 (5.19%)  32/549 (5.83%)  28/558 (5.02%)  7/150 (4.67%)  4/152 (2.63%)  12/299 (4.01%)  14/251 (5.58%) 
Depression  1  34/540 (6.30%)  40/549 (7.29%)  34/558 (6.09%)  8/150 (5.33%)  5/152 (3.29%)  9/299 (3.01%)  9/251 (3.59%) 
Confusional state  1  0/540 (0.00%)  0/549 (0.00%)  0/558 (0.00%)  5/150 (3.33%)  9/152 (5.92%)  4/299 (1.34%)  3/251 (1.20%) 
Respiratory, thoracic and mediastinal disorders               
Cough  1  33/540 (6.11%)  29/549 (5.28%)  19/558 (3.41%)  9/150 (6.00%)  4/152 (2.63%)  12/299 (4.01%)  6/251 (2.39%) 
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
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.
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.
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
Layout table for Results Point of Contact information
Name/Title: Biogen Study Medical Director
Organization: Biogen
Phone: 866-633-4636
EMail: clinicaltrials@biogen.com
Layout table for additonal information
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02477800    
Other Study ID Numbers: 221AD301
2015-000966-72 ( EudraCT Number )
First Submitted: June 18, 2015
First Posted: June 23, 2015
Results First Submitted: July 1, 2021
Results First Posted: September 2, 2021
Last Update Posted: September 2, 2021