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221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (EMERGE)

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: NCT02484547
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 29, 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 1643
Recruitment Details Participants were enrolled at 181 investigative sites in the United States, Belgium, Canada, Finland, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, and Switzerland from 15 September 2015 to 13 July 2018.
Pre-assignment Details A total of 1643 participants with Alzhiemer's disease were enrolled and randomized in the study. Of these, 1638 participants received the study drug in placebo-controlled (PC) period. After completing PC period, 771 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 548 543 547 0 0 0 0
Completed 288 291 295 0 0 0 0
Not Completed 260 252 252 0 0 0 0
Reason Not Completed
Adverse Event             10             13             20             0             0             0             0
Change of Treatment             0             0             1             0             0             0             0
Consent Withdrawn             15             32             26             0             0             0             0
Death             5             0             6             0             0             0             0
Disease Progression             2             0             1             0             0             0             0
Investigator Decision             2             2             5             0             0             0             0
Lost to Follow-up             3             1             3             0             0             0             0
Relocation             1             1             1             0             0             0             0
Study Visit Burden             2             8             5             0             0             0             0
Withdrawal by Parent/Guardian             4             1             1             0             0             0             0
Reason not Specified             216             194             183             0             0             0             0
Period Title: Long-Term Extension Period
Started 0 0 0 131 [1] 132 [2] 251 [3] 257 [4]
Completed 0 0 0 0 0 0 0
Not Completed 0 0 0 131 132 251 257
Reason Not Completed
Adverse Event             0             0             0             0             1             3             2
Death             0             0             0             0             0             3             0
Disease Progression             0             0             0             0             2             4             0
Lost to Follow-up             0             0             0             1             1             2             0
Loss of Capacity             0             0             0             0             1             0             0
Change of Treatment             0             0             0             0             0             0             1
Consent Withdrawn             0             0             0             6             7             13             17
Investigator Decision             0             0             0             2             1             0             1
Relocation             0             0             0             1             1             0             0
Study Visit Burden             0             0             0             2             0             0             3
Withdrawal by Parent/Guardian             0             0             0             0             1             3             2
Reason not Specified             0             0             0             119             117             223             231
[1]
11 PC completers did not enter LTE.
[2]
14 PC completers did not enter LTE.
[3]
40 PC completers did not enter LTE.
[4]
38 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 548 543 547 1638
Hide Baseline Analysis Population Description
Intent-to-Treat (ITT) population was defined as all randomized participants who had received at least one dose of study treatment (Aducanumab or Placebo).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 548 participants 543 participants 547 participants 1638 participants
70.8  (7.40) 70.6  (7.45) 70.6  (7.47) 70.7  (7.43)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 548 participants 543 participants 547 participants 1638 participants
Female
290
  52.9%
269
  49.5%
284
  51.9%
843
  51.5%
Male
258
  47.1%
274
  50.5%
263
  48.1%
795
  48.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 548 participants 543 participants 547 participants 1638 participants
American Indian or Alaska Native
1
   0.2%
0
   0.0%
0
   0.0%
1
   0.1%
Asian
47
   8.6%
39
   7.2%
42
   7.7%
128
   7.8%
Black or African American
1
   0.2%
6
   1.1%
4
   0.7%
11
   0.7%
White
431
  78.6%
432
  79.6%
422
  77.1%
1285
  78.4%
Not Reported Due to Confidentiality Regulations
67
  12.2%
65
  12.0%
75
  13.7%
207
  12.6%
Other
1
   0.2%
1
   0.2%
3
   0.5%
5
   0.3%
Unknown
0
   0.0%
0
   0.0%
1
   0.2%
1
   0.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Ethinicity Number Analyzed 548 participants 543 participants 547 participants 1638 participants
Hispanic or Latino
22
   4.0%
22
   4.1%
23
   4.2%
67
   4.1%
Not Hispanic or Latino
470
  85.8%
470
  86.6%
461
  84.3%
1401
  85.5%
Not Reported Due to Confidentiality Regulations
56
  10.2%
51
   9.4%
62
  11.3%
169
  10.3%
Unknown
0
   0.0%
0
   0.0%
1
   0.2%
1
   0.1%
1.Primary Outcome
Title Change From Baseline in Clinical Dementia Rating Scale - 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 288 290 299
Mean (Standard Error)
Unit of Measure: score on a scale
1.74  (0.115) 1.47  (0.116) 1.35  (0.115)
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 0.0901
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -0.26
Confidence Interval (2-Sided) 95%
-0.569 to 0.041
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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0120
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-0.694 to -0.086
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 288 293 299
Mean (Standard Error)
Unit of Measure: score on a scale
-3.3  (0.22) -3.3  (0.22) -2.7  (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 0.7578
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.65 to 0.48
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 0.0493
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.6
Confidence Interval (2-Sided) 95%
0.00 to 1.13
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) 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 287 289 293
Mean (Standard Error)
Unit of Measure: score on a scale
5.162  (0.4049) 4.461  (0.4074) 3.763  (0.4036)
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 ADASCog 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 0.1962
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -0.701
Confidence Interval (2-Sided) 95%
-1.7649 to 0.3627
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 ADASCog 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 0.0097
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -1.400
Confidence Interval (2-Sided) 95%
-2.4596 to -0.3396
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 283 286 295
Mean (Standard Error)
Unit of Measure: score on a scale
-4.3  (0.38) -3.5  (0.38) -2.5  (0.38)
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 and BIIB037 High Dose), difference from Placebo,95% CI and p-value at each time point were based on an MMRM model, with change from baseline in ADCSADL-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 0.1515
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-0.27 to 1.73
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 and BIIB037 High Dose), difference from Placebo,95% CI and p-value at each time point were based on an MMRM model, with change from baseline in ADCSADL-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 0.0006
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
0.75 to 2.74
Estimation Comments [Not Specified]
Time Frame From First Dose to End of Study (up to 4 years)
Adverse Event Reporting Description The safety population was defined as all randomised participants who had received at least one dose of study treatment. In PC period, 1 participant randomized to placebo, inadvertently received 1 or more doses of active treatment (Low Dose) 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   5/547 (0.91%)   0/544 (0.00%)   6/547 (1.10%)   0/131 (0.00%)   0/132 (0.00%)   3/251 (1.20%)   0/257 (0.00%) 
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   81/547 (14.81%)   72/544 (13.24%)   73/547 (13.35%)   15/131 (11.45%)   9/132 (6.82%)   25/251 (9.96%)   25/257 (9.73%) 
Blood and lymphatic system disorders               
Iron deficiency anaemia † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Cardiac disorders               
Acute coronary syndrome † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Acute left ventricular failure † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Acute myocardial infarction † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  1/257 (0.39%) 
Angina pectoris † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Angina unstable † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Aortic valve incompetence † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Atrial fibrillation † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Atrial flutter † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Atrioventricular block second degree † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Bradycardia † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cardiac arrest † 1  0/547 (0.00%)  0/544 (0.00%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cardiac failure congestive † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Coronary artery disease † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  2/257 (0.78%) 
Ischaemic cardiomyopathy † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Myocardial infarction † 1  2/547 (0.37%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Sinus bradycardia † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Sinus node dysfunction † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Sinus tachycardia † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Stress cardiomyopathy † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Supraventricular extrasystoles † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Ear and labyrinth disorders               
Deafness bilateral † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Meniere's disease † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Vertigo † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Endocrine disorders               
Inappropriate antidiuretic hormone secretion † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Eye disorders               
Age-related macular degeneration † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Cataract nuclear † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Retinal detachment † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Vitreous floaters † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrointestinal disorders               
Abdominal pain † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Acquired oesophageal web † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Barrett's oesophagus † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Colitis † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Colitis ischaemic † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Constipation † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Diarrhoea † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Diverticular perforation † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Diverticulum intestinal haemorrhagic † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Duodenal ulcer perforation † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Dysphagia † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Femoral hernia strangulated † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastritis † 1  1/547 (0.18%)  0/544 (0.00%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrointestinal haemorrhage † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrointestinal necrosis † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrooesophageal reflux disease † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Haemorrhoidal haemorrhage † 1  0/547 (0.00%)  2/544 (0.37%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Haemorrhoids † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Ileus † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Inguinal hernia † 1  0/547 (0.00%)  2/544 (0.37%)  3/547 (0.55%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Intestinal obstruction † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Intestinal perforation † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Large intestine polyp † 1  2/547 (0.37%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Nausea † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Obstructive pancreatitis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pancreatitis † 1  1/547 (0.18%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pancreatitis acute † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pneumoperitoneum † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Rectal prolapse † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Vomiting † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
General disorders               
Asthenia † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Chest pain † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  1/257 (0.39%) 
Death † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Discomfort † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gait disturbance † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  2/257 (0.78%) 
Medical device site joint pain † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Non-cardiac chest pain † 1  2/547 (0.37%)  1/544 (0.18%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Pyrexia † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hepatobiliary disorders               
Cholecystitis † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cholecystitis acute † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cholelithiasis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hepatitis acute † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Jaundice † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Immune system disorders               
Hypersensitivity † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Infections and infestations               
Appendicitis † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Bacterial infection † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Bronchitis † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cellulitis † 1  0/547 (0.00%)  1/544 (0.18%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cystitis klebsiella † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Erysipelas † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastroenteritis † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Gastroenteritis viral † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Human anaplasmosis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Lymphangitis † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Otitis media † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Pneumonia † 1  2/547 (0.37%)  2/544 (0.37%)  1/547 (0.18%)  1/131 (0.76%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Pneumonia bacterial † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pneumonia influenzal † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Pneumonia respiratory syncytial viral † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pulmonary sepsis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Sepsis † 1  0/547 (0.00%)  0/544 (0.00%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Urinary tract infection † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Urosepsis † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Injury, poisoning and procedural complications               
Accident † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Accidental overdose † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Alcohol poisoning † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Animal attack † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Animal scratch † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Ankle fracture † 1  2/547 (0.37%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Bone contusion † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cardiac contusion † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Concussion † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Craniocerebral injury † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Epiphyseal fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Fall † 1  12/547 (2.19%)  9/544 (1.65%)  4/547 (0.73%)  2/131 (1.53%)  1/132 (0.76%)  1/251 (0.40%)  6/257 (2.33%) 
Femoral neck fracture † 1  3/547 (0.55%)  2/544 (0.37%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Foot fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrointestinal procedural complication † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hand fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Head injury † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hip fracture † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  2/257 (0.78%) 
Humerus fracture † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Joint dislocation † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Lower limb fracture † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Lumbar vertebral fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pelvic fracture † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pubis fracture † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Pulmonary contusion † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Radius fracture † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Rib fracture † 1  5/547 (0.91%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Road traffic accident † 1  1/547 (0.18%)  2/544 (0.37%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Skin laceration † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Skull fracture † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Spinal fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Subdural haematoma † 1  0/547 (0.00%)  3/544 (0.55%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Thoracic vertebral fracture † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Upper limb fracture † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Wrist fracture † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Investigations               
Weight decreased † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Metabolism and nutrition disorders               
Dehydration † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hyperglycaemia † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hypoglycaemia † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hyponatraemia † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Musculoskeletal and connective tissue disorders               
Arthritis † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Back pain † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Bursitis † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Intervertebral disc protrusion † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Muscular weakness † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Musculoskeletal pain † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Musculoskeletal stiffness † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Osteoarthritis † 1  2/547 (0.37%)  3/544 (0.55%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Osteonecrosis † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Rhabdomyolysis † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Spinal osteoarthritis † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Vertebral foraminal stenosis † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Adenocarcinoma of colon † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  1/131 (0.76%)  1/132 (0.76%)  1/251 (0.40%)  0/257 (0.00%) 
Adenocarcinoma pancreas † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Basal cell carcinoma † 1  0/547 (0.00%)  2/544 (0.37%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Bladder papilloma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Breast cancer † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cholangiocarcinoma † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Cholesteatoma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Diffuse large b-cell lymphoma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Endometrial adenocarcinoma † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Endometrial cancer † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastric cancer † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gastrointestinal neoplasm † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Invasive ductal breast carcinoma † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Invasive lobular breast carcinoma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Lung adenocarcinoma stage iv † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Lung neoplasm malignant † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Malignant melanoma † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Malignant melanoma in situ † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Medullary thyroid cancer † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Metastatic neoplasm † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Oesophageal carcinoma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Ovarian cancer † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pancreatic carcinoma metastatic † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pleural mesothelioma † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Prostate cancer † 1  1/547 (0.18%)  2/544 (0.37%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Prostatic adenoma † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Salivary gland cancer † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Small cell lung cancer † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Squamous cell carcinoma † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Squamous cell carcinoma of the oral cavity † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
T-cell lymphoma † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Thymoma malignant † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Nervous system disorders               
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits † 1  0/547 (0.00%)  4/544 (0.74%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Amyloid related imaging abnormality-oedema/effusion † 1  1/547 (0.18%)  5/544 (0.92%)  8/547 (1.46%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Carpal tunnel syndrome † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Cerebellar infarction † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cerebral haematoma † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cerebral haemorrhage † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  1/132 (0.76%)  0/251 (0.00%)  0/257 (0.00%) 
Cerebral infarction † 1  2/547 (0.37%)  2/544 (0.37%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cerebrovascular accident † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Dementia alzheimer's type † 1  2/547 (0.37%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Dizziness † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Embolic cerebral infarction † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Embolic stroke † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Encephalopathy † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Focal dyscognitive seizures † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Generalised tonic-clonic seizure † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Guillain-barre syndrome † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Headache † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Intracranial venous sinus thrombosis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Ischaemic stroke † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  1/251 (0.40%)  1/257 (0.39%) 
Lacunar infarction † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Loss of consciousness † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Memory impairment † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Metabolic encephalopathy † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Presyncope † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Quadriparesis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Seizure † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Sensorimotor disorder † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Superficial siderosis of central nervous system † 1  0/547 (0.00%)  1/544 (0.18%)  3/547 (0.55%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Syncope † 1  3/547 (0.55%)  2/544 (0.37%)  4/547 (0.73%)  0/131 (0.00%)  1/132 (0.76%)  2/251 (0.80%)  2/257 (0.78%) 
Thrombotic stroke † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Toxic encephalopathy † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Transient ischaemic attack † 1  1/547 (0.18%)  0/544 (0.00%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Psychiatric disorders               
Agitation † 1  3/547 (0.55%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Anxiety † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Behaviour disorder † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Bipolar disorder † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Confusional state † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Delirium † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Delusion † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Depression † 1  2/547 (0.37%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Intentional self-injury † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Mania † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Mental status changes † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Neuropsychiatric symptoms † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Psychotic disorder † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Somatic symptom disorder † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Suicidal ideation † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Suicide attempt † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Renal and urinary disorders               
Acute kidney injury † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Calculus bladder † 1  0/547 (0.00%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Nephrolithiasis † 1  0/547 (0.00%)  1/544 (0.18%)  1/547 (0.18%)  1/131 (0.76%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Prerenal failure † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Renal failure † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Urethral disorder † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Urethral stenosis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Urinary retention † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Reproductive system and breast disorders               
Adnexa uteri cyst † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Benign prostatic hyperplasia † 1  1/547 (0.18%)  1/544 (0.18%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Cervical polyp † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Gynaecomastia † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  1/131 (0.76%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Ovarian cyst † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Spermatic cord cyst † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Asthma † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Haemothorax † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Laryngeal oedema † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Lung perforation † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Pneumonia aspiration † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Pneumothorax † 1  0/547 (0.00%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  1/257 (0.39%) 
Pulmonary embolism † 1  1/547 (0.18%)  0/544 (0.00%)  2/547 (0.37%)  0/131 (0.00%)  0/132 (0.00%)  1/251 (0.40%)  0/257 (0.00%) 
Respiratory failure † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Vascular disorders               
Aortic aneurysm rupture † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Aortic stenosis † 1  0/547 (0.00%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Deep vein thrombosis † 1  1/547 (0.18%)  1/544 (0.18%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hypertension † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hypertensive crisis † 1  2/547 (0.37%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hypertensive urgency † 1  1/547 (0.18%)  0/544 (0.00%)  1/547 (0.18%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Hypotension † 1  1/547 (0.18%)  0/544 (0.00%)  0/547 (0.00%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (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   353/547 (64.53%)   385/544 (70.77%)   428/547 (78.24%)   55/131 (41.98%)   56/132 (42.42%)   87/251 (34.66%)   107/257 (41.63%) 
Gastrointestinal disorders               
Diarrhoea † 1  29/547 (5.30%)  38/544 (6.99%)  42/547 (7.68%)  3/131 (2.29%)  7/132 (5.30%)  9/251 (3.59%)  6/257 (2.33%) 
Nausea † 1  27/547 (4.94%)  29/544 (5.33%)  31/547 (5.67%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
General disorders               
Fatigue † 1  37/547 (6.76%)  27/544 (4.96%)  34/547 (6.22%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Infections and infestations               
Nasopharyngitis † 1  91/547 (16.64%)  71/544 (13.05%)  89/547 (16.27%)  6/131 (4.58%)  7/132 (5.30%)  18/251 (7.17%)  19/257 (7.39%) 
Upper respiratory tract infection † 1  41/547 (7.50%)  42/544 (7.72%)  38/547 (6.95%)  8/131 (6.11%)  2/132 (1.52%)  13/251 (5.18%)  11/257 (4.28%) 
Urinary tract infection † 1  36/547 (6.58%)  39/544 (7.17%)  29/547 (5.30%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Injury, poisoning and procedural complications               
Fall † 1  62/547 (11.33%)  59/544 (10.85%)  73/547 (13.35%)  13/131 (9.92%)  7/132 (5.30%)  15/251 (5.98%)  32/257 (12.45%) 
Musculoskeletal and connective tissue disorders               
Arthralgia † 1  31/547 (5.67%)  17/544 (3.13%)  34/547 (6.22%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Back pain † 1  36/547 (6.58%)  38/544 (6.99%)  42/547 (7.68%)  8/131 (6.11%)  3/132 (2.27%)  9/251 (3.59%)  10/257 (3.89%) 
Nervous system disorders               
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits † 1  37/547 (6.76%)  86/544 (15.81%)  106/547 (19.38%)  18/131 (13.74%)  11/132 (8.33%)  12/251 (4.78%)  21/257 (8.17%) 
Amyloid related imaging abnormality-oedema/effusion † 1  12/547 (2.19%)  138/544 (25.37%)  183/547 (33.46%)  23/131 (17.56%)  31/132 (23.48%)  11/251 (4.38%)  22/257 (8.56%) 
Dizziness † 1  43/547 (7.86%)  42/544 (7.72%)  55/547 (10.05%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Headache † 1  84/547 (15.36%)  109/544 (20.04%)  107/547 (19.56%)  10/131 (7.63%)  13/132 (9.85%)  20/251 (7.97%)  19/257 (7.39%) 
Superficial siderosis of central nervous system † 1  14/547 (2.56%)  51/544 (9.38%)  71/547 (12.98%)  13/131 (9.92%)  17/132 (12.88%)  4/251 (1.59%)  10/257 (3.89%) 
Psychiatric disorders               
Anxiety † 1  21/547 (3.84%)  30/544 (5.51%)  19/547 (3.47%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Confusional state † 1  15/547 (2.74%)  16/544 (2.94%)  28/547 (5.12%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Depression † 1  28/547 (5.12%)  29/544 (5.33%)  23/547 (4.20%)  0/131 (0.00%)  0/132 (0.00%)  0/251 (0.00%)  0/257 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Cough † 1  28/547 (5.12%)  24/544 (4.41%)  33/547 (6.03%)  4/131 (3.05%)  4/132 (3.03%)  7/251 (2.79%)  14/257 (5.45%) 
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
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02484547    
Other Study ID Numbers: 221AD302
2015-000967-15 ( EudraCT Number )
First Submitted: June 18, 2015
First Posted: June 29, 2015
Results First Submitted: July 1, 2021
Results First Posted: September 2, 2021
Last Update Posted: September 2, 2021