Alzheimer's Disease
Conditions
Keywords
Aducanumab, BIIB037
Brief summary
The primary objective of the study is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with early AD. Secondary objectives are to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale (13 items) \[ADAS-Cog 13\], and AD Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) \[ADCS-ADL-MCI\].
Interventions
Low dose
DRUGPlacebo
Placebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must meet all of the following clinical criteria for MCI due to AD or mild AD and must have: * A Clinical Dementia Rating (CDR)-Global Score of 0.5. * Objective evidence of cognitive impairment at screening * An MMSE score between 24 and 30 (inclusive) * Must have a positive amyloid Positron Emission Tomography (PET) scan * Must consent to apolipoprotein E (ApoE) genotyping * If using drugs to treat symptoms related to AD, doses must be stable for at least 8 weeks prior to screening visit 1 * Must have a reliable informant or caregiver Key
Exclusion criteria
* Any medical or neurological condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment * Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year * Clinically significant unstable psychiatric illness in past 6 months * History of unstable angina, myocardial infarction, advanced chronic heart failure, or clinically significant conduction abnormalities within 1 year prior to Screening * Indication of impaired renal or liver function * Have human immunodeficiency virus (HIV) infection * Have a significant systematic illness or infection in past 30 days * Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities * Any contraindications to brain magnetic resonance imaging (MRI) or PET scans * Alcohol or substance abuse in past 1 year * Taking blood thinners (except for aspirin at a prophylactic dose or less) NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78 | Baseline, Week 78 | CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic patient examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. Prespecified severity anchors range from none = 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). Sum of boxes scoring methodology sums the score for each of the 6 domains and provides a value ranging from 0 to 18 that can change in increments of 0.5 or greater. Higher scores indicate greater disease severity. Mixed model for repeated measures (MMRM) analysis was used to analyze change from baseline in CDR-SB. A positive change from baseline indicates clinical decline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mini Mental State Examination (MMSE) Score at Week 78 | Baseline, Week 78 | The MMSE is a widely used performance-based test of global cognitive status. It consists of 11 tasks that assess orientation, word recall, attention and calculation, language abilities, and visuospatial functions. The scores from the 11 tests are combined to obtain the total score, which ranges from 0 to 30, with lower scores over time indicating increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in MMSE. A negative change from baseline indicates clinical decline. |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) at Week 78 | Baseline, Week 78 | ADAS-Cog13 comprises both cognitive tasks and clinical ratings of cognitive performance. The scale items capture word recall, ability to follow commands, the ability to correctly copy or draw an image, naming, the ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure for delayed word recall and concentration/distractibility. The total score ranges from 0 to 85. An increase in score over time indicates increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in ADAS-Cog 13. A positive change from baseline indicates clinical decline. |
| Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL-MCI) Score at Week 78 | Baseline, Week 78 | The ADCS-ADL-MCI consists of 17 instrumental items (e.g., shopping, preparing meals, using household appliances) and 1 basic item (getting dressed). Ratings reflect caregiver observations about the patient's actual functioning over the previous month and provide an assessment of change in the functional state of the participant over time. The total score ranges from 0 to 53, with lower values over time reflecting functional deterioration. MMRM analysis was used to analyze change from baseline in ADAS-ADL-MCI. A negative change from baseline indicates clinical decline. |
Countries
Belgium, Canada, Finland, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, Switzerland, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (PC Period) 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. | 548 |
| BIIB037 Low Dose (PC Period) 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. | 543 |
| BIIB037 High Dose (PC Period) 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. | 547 |
| Total | 1,638 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Long-Term Extension Period | Adverse Event | 0 | 0 | 0 | 0 | 1 | 3 | 2 |
| Long-Term Extension Period | Change of Treatment | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Long-Term Extension Period | Consent Withdrawn | 0 | 0 | 0 | 6 | 7 | 13 | 17 |
| Long-Term Extension Period | Death | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| Long-Term Extension Period | Disease Progression | 0 | 0 | 0 | 0 | 2 | 4 | 0 |
| Long-Term Extension Period | Investigator Decision | 0 | 0 | 0 | 2 | 1 | 0 | 1 |
| Long-Term Extension Period | Loss of Capacity | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Long-Term Extension Period | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 | 2 | 0 |
| Long-Term Extension Period | Reason not Specified | 0 | 0 | 0 | 119 | 117 | 223 | 231 |
| Long-Term Extension Period | Relocation | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Long-Term Extension Period | Study Visit Burden | 0 | 0 | 0 | 2 | 0 | 0 | 3 |
| Long-Term Extension Period | Withdrawal by Parent/Guardian | 0 | 0 | 0 | 0 | 1 | 3 | 2 |
| Placebo-Controlled Period | Adverse Event | 10 | 13 | 20 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Change of Treatment | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Consent Withdrawn | 15 | 32 | 26 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Death | 5 | 0 | 6 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Disease Progression | 2 | 0 | 1 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Investigator Decision | 2 | 2 | 5 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Lost to Follow-up | 3 | 1 | 3 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Reason not Specified | 216 | 194 | 183 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Relocation | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Study Visit Burden | 2 | 8 | 5 | 0 | 0 | 0 | 0 |
| Placebo-Controlled Period | Withdrawal by Parent/Guardian | 4 | 1 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (PC Period) | Total | BIIB037 Low Dose (PC Period) | BIIB037 High Dose (PC Period) |
|---|---|---|---|---|
| Age, Continuous | 70.8 years STANDARD_DEVIATION 7.4 | 70.7 years STANDARD_DEVIATION 7.43 | 70.6 years STANDARD_DEVIATION 7.45 | 70.6 years STANDARD_DEVIATION 7.47 |
| Race/Ethnicity, Customized Ethinicity Hispanic or Latino | 22 Participants | 67 Participants | 22 Participants | 23 Participants |
| Race/Ethnicity, Customized Ethinicity Not Hispanic or Latino | 470 Participants | 1401 Participants | 470 Participants | 461 Participants |
| Race/Ethnicity, Customized Ethinicity Not Reported Due to Confidentiality Regulations | 56 Participants | 169 Participants | 51 Participants | 62 Participants |
| Race/Ethnicity, Customized Ethinicity Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 47 Participants | 128 Participants | 39 Participants | 42 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 11 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Not Reported Due to Confidentiality Regulations | 67 Participants | 207 Participants | 65 Participants | 75 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 431 Participants | 1285 Participants | 432 Participants | 422 Participants |
| Sex: Female, Male Female | 290 Participants | 843 Participants | 269 Participants | 284 Participants |
| Sex: Female, Male Male | 258 Participants | 795 Participants | 274 Participants | 263 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 547 | 0 / 544 | 6 / 547 | 0 / 131 | 0 / 132 | 3 / 251 | 0 / 257 |
| other Total, other adverse events | 353 / 547 | 385 / 544 | 428 / 547 | 55 / 131 | 56 / 132 | 87 / 251 | 107 / 257 |
| serious Total, serious adverse events | 81 / 547 | 72 / 544 | 73 / 547 | 15 / 131 | 9 / 132 | 25 / 251 | 25 / 257 |
Outcome results
Primary
Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78
CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic patient examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. Prespecified severity anchors range from none = 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). Sum of boxes scoring methodology sums the score for each of the 6 domains and provides a value ranging from 0 to 18 that can change in increments of 0.5 or greater. Higher scores indicate greater disease severity. Mixed model for repeated measures (MMRM) analysis was used to analyze change from baseline in CDR-SB. A positive change from baseline indicates clinical decline.
Time frame: Baseline, Week 78
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PC Period) | Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78 | 1.74 score on a scale | Standard Error 0.115 |
| BIIB037 Low Dose (PC Period) | Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78 | 1.47 score on a scale | Standard Error 0.116 |
| BIIB037 High Dose (PC Period) | Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78 | 1.35 score on a scale | Standard Error 0.115 |
Comparison: 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.p-value: 0.090195% CI: [-0.569, 0.041]MMRM
Comparison: 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.p-value: 0.01295% CI: [-0.694, -0.086]MMRM
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) at Week 78
ADAS-Cog13 comprises both cognitive tasks and clinical ratings of cognitive performance. The scale items capture word recall, ability to follow commands, the ability to correctly copy or draw an image, naming, the ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure for delayed word recall and concentration/distractibility. The total score ranges from 0 to 85. An increase in score over time indicates increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in ADAS-Cog 13. A positive change from baseline indicates clinical decline.
Time frame: Baseline, Week 78
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PC Period) | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) at Week 78 | 5.162 score on a scale | Standard Error 0.4049 |
| BIIB037 Low Dose (PC Period) | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) at Week 78 | 4.461 score on a scale | Standard Error 0.4074 |
| BIIB037 High Dose (PC Period) | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) at Week 78 | 3.763 score on a scale | Standard Error 0.4036 |
Comparison: 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.p-value: 0.196295% CI: [-1.7649, 0.3627]MMRM
Comparison: 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.p-value: 0.009795% CI: [-2.4596, -0.3396]MMRM
Secondary
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
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PC Period) | 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 | -4.3 score on a scale | Standard Error 0.38 |
| BIIB037 Low Dose (PC Period) | 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 | -3.5 score on a scale | Standard Error 0.38 |
| BIIB037 High Dose (PC Period) | 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 | -2.5 score on a scale | Standard Error 0.38 |
Comparison: 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.p-value: 0.151595% CI: [-0.27, 1.73]MMRM
Comparison: 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.p-value: 0.000695% CI: [0.75, 2.74]MMRM
Secondary
Change From Baseline in Mini Mental State Examination (MMSE) Score at Week 78
The MMSE is a widely used performance-based test of global cognitive status. It consists of 11 tasks that assess orientation, word recall, attention and calculation, language abilities, and visuospatial functions. The scores from the 11 tests are combined to obtain the total score, which ranges from 0 to 30, with lower scores over time indicating increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in MMSE. A negative change from baseline indicates clinical decline.
Time frame: Baseline, Week 78
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PC Period) | Change From Baseline in Mini Mental State Examination (MMSE) Score at Week 78 | -3.3 score on a scale | Standard Error 0.22 |
| BIIB037 Low Dose (PC Period) | Change From Baseline in Mini Mental State Examination (MMSE) Score at Week 78 | -3.3 score on a scale | Standard Error 0.22 |
| BIIB037 High Dose (PC Period) | Change From Baseline in Mini Mental State Examination (MMSE) Score at Week 78 | -2.7 score on a scale | Standard Error 0.21 |
Comparison: 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.p-value: 0.757895% CI: [-0.65, 0.48]MMRM
Comparison: 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.p-value: 0.049395% CI: [0, 1.13]MMRM