221AD301

Biogen

250 Binney Street, Cambridge, United States, 02142

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com

No

No

No

Final

08 Aug 2019

No

Yes

08 Aug 2019

Yes

The primary objective of this study was to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in subjects with early Alzheimer's Disease (AD).

Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.

13 Aug 2015

Yes

Yes

United States: 766

Italy: 116

Spain: 105

Australia: 102

Japan: 100

Germany: 97

Canada: 84

United Kingdom: 81

France: 60

Korea, Republic of: 50

Portugal: 47

Denmark: 23

Taiwan: 13

Austria: 9

1653

457

0

0

0

0

0

0

371

1272

10

Placebo-Controlled Period

Randomised - controlled

Yes

Placebo

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

Long Term Extension Period

Randomised - controlled

Yes

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

BIIB037

Aducanumab

Concentrate for solution for infusion

Intravenous use

Intravenous infusion, once every 4 weeks.

Placebo (PC Period)

BIIB037 Low Dose (PC Period)

BIIB037 High Dose (PC Period)

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)

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 subject’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 analyse change from baseline in CDR-SB. A positive change from baseline indicates clinical decline. Intent-to-Treat (ITT) population. n=number of subjects analysed at specific timepoint.

Primary

Baseline, Week 78

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.

Placebo (PC Period) v BIIB037 Low Dose (PC Period)

1092

Pre-specified

-0.18

2-sided

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.

Placebo (PC Period) v BIIB037 High Dose (PC Period)

1100

Pre-specified

0.03

2-sided

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 analyse change from baseline in MMSE. A negative change from baseline indicates clinical decline. ITT is defined as all randomised subjects who had received at least one dose of study treatment (Aducanumab or Placebo). Here, 'n' signifies number of subjects analysed at specific timepoint.

Secondary

Baseline, Week 78

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.

Placebo (PC Period) v BIIB037 High Dose (PC Period)

1100

Pre-specified

-0.1

2-sided

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.

Placebo (PC Period) v BIIB037 Low Dose (PC Period)

1092

Pre-specified

0.2

2-sided

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 analyse change from baseline in ADAS-Cog 13. A positive change from baseline indicates clinical decline. ITT is defined as all randomised subjects who had received at least one dose of study treatment (Aducanumab or Placebo). Here, 'n' signifies number of subjects analysed at specific timepoint.

Secondary

Baseline, Week 78

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.

Placebo (PC Period) v BIIB037 High Dose (PC Period)

1100

Pre-specified

-0.588

2-sided

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.

Placebo (PC Period) v BIIB037 Low Dose (PC Period)

1092

Pre-specified

-0.583

2-sided

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 analyse change from baseline in ADAS-ADL-MCI. A negative change from baseline indicates clinical decline. ITT is defined as all randomised subjects who had received at least one dose of study treatment (Aducanumab or Placebo). Here, 'n' signifies number of subjects analysed at specific timepoint.

Secondary

Baseline, Week 78

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.

Placebo (PC Period) v BIIB037 High Dose (PC Period)

1100

Pre-specified

0.7

2-sided

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.

Placebo (PC Period) v BIIB037 Low Dose (PC Period)

1092

Pre-specified

0.7

2-sided

From First Dose to End of Study (up to 4 years)

Safety population was all randomised subjects who received at least one dose of study treatment. In PC period, 5 subjects randomised to placebo, inadvertently received 1 or more doses of active treatment during the PC period. For subjects affected, a subject was counted only once within each system organ class/preferred term/study period.

22.0

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)