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

• ClinicalTrials.gov Identifier: NCT02477800
• Recruitment Status: Terminated
• First Posted: June 23, 2015
• Results First Posted: September 2, 2021
• Last Update Posted: September 2, 2021
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: June 18, 2015
• First Posted Date: June 23, 2015
• Results First Submitted Date: July 1, 2021
• Results First Posted Date: September 2, 2021
• Last Update Posted Date: September 2, 2021
• Actual Study Start Date: August 13, 2015
• Actual Primary Completion Date: August 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 9, 2021)

Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 78 [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: June 18, 2015): Change from baseline in CDR-SB score [ Time Frame: Week 78 ]

Current Secondary Outcome Measures (submitted: August 9, 2021)

• Change From Baseline in Mini-Mental State Examination (MMSE) Score at Week 78 [ Time Frame: 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) Score at Week 78 [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: June 18, 2015)

• Change from baseline in MMSE score [ Time Frame: Week 78 ]
• Change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 items) (ADAS-Cog 13) [ Time Frame: Week 78 ]
• Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL-MCI) score [ Time Frame: Week 78 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease
• Official Title: A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease
• 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].
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: Aducanumab (BIIB037)
  Low dose
• Drug: Aducanumab (BIIB037)
  High dose
• Drug: Placebo
  Placebo

Study Arms

• Experimental: Low Dose
  Monthly intravenous (IV) infusion
  Interventions:

  • Drug: Aducanumab (BIIB037)
  • Drug: Placebo
• Experimental: High Dose
  Monthly intravenous (IV) infusion
  Interventions:

  • Drug: Aducanumab (BIIB037)
  • Drug: Placebo

• Publications *: Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy J, Forrestal F, Tian Y, Umans K, Wang G, Singhal P, Budd Haeberlein S, Smirnakis K. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022 Jan 1;79(1):13-21. doi: 10.1001/jamaneurol.2021.4161.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 9, 2021): 1653
• Original Estimated Enrollment (submitted: June 18, 2015): 1350
• Actual Study Completion Date: August 8, 2019
• Actual Primary Completion Date: August 8, 2019 (Final data collection date for primary outcome measure)

Eligibility 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/Exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Portugal, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Czech Republic, Hungary

Administrative Information

• NCT Number: NCT02477800
• Other Study ID Numbers: 221AD301; 2015-000966-72 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Same as current
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: August 2021