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


About this study

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].

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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:

Medical History

  • Any uncontrolled medical or neurological/neurodegenerative condition (other than AD) that, in the opinion of the Investigator, might be a contributing cause of the subject’s cognitive impairment (e.g., substance abuse, vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, Lewy body dementia, fronto-temporal dementia, head trauma).
  • Clinically significant unstable psychiatric illness (e.g., uncontrolled major depression, uncontrolled schizophrenia, uncontrolled bipolar affective disorder) within 6 months prior to Screening.
  • Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening.
  • Brain MRI performed at Screening (per centrally read MRI) that shows evidence of any of the following:
  • Acute or sub-acute hemorrhage.
  • Prior macrohemorrhage (defined as 1 cm in diameter on T2* sequence) or prior subarachnoid hemorrhage unless it can be documented that the finding is not due to an underlying structural or vascular abnormality (i.e., finding does not suggest subject is at risk of recurrent hemorrhage).
  • Greater than 4 microhemorrhages (defined as 1 cm in diameter on T2* sequence).
  • Cortical infarct (defined as >1.5 cm in diameter; irrespective of anatomic location).
  • 1  lacunar infarct (defined as 1.5 cm in diameter).
  • Superficial siderosis.
  • History of diffuse white matter disease as defined by a score of 3 on the age-related white matter changes scale [Wahlund 2001].
  • Any finding that, in the opinion of the Investigator, might be a contributing cause of subject’s dementia, might pose a risk to the subject, or might prevent a satisfactory MRI assessment for safety monitoring.
  • History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator.
  • Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be controlled or adequately managed.
  • History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening.
  • Clinically significant 12-lead ECG abnormalities, as determined by the Investigator.
  • Uncontrolled hypertension defined as: average of 3 systolic blood pressure [SBP]/diastolic blood pressure [DBP] readings >165 mmHg and/or >100 mmHg at Screening (blood pressure measurements exceeding these limits may be repeated as
  • warranted by the Investigator, but values must be within the specified limits for the subject to be eligible for the study), or persistent SBP/DBP readings >180 mmHg and/or >100 mmHg 3 months prior to randomization (Day 1) that, in the opinion of the Investigator, are indicative of chronic uncontrolled hypertension.
  • History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:
  • Subjects with cancers in remission more than 5 years prior to Screening.
  • Subjects with a history of excised or treated basal cell or squamous carcinoma of the skin.
  • Subjects with localized prostate cancer with treatment cycles that completed at least 6 months prior to Screening.
  • History of seizure within 10 years prior to Screening.
  • Indication of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., repeated values of aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≥ 2 × the upper limit of normal).
  • History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.
  • Recent history (within 1 year of Screening) of alcohol or substance abuse as determined by the Investigator, a positive urine drug (due to non-prescription drug) or alcohol test at Screening, or use of cannabinoids (prescription or recreational).
  • Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) within 30 days prior to or during Screening.
  • History of or known seropositivity for human immunodeficiency virus (HIV).
  • History of or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for both hepatitis B surface antigen AND hepatitis B core antibody).
  • History of severe allergic or anaphylactic reactions, or history of hypersensitivity to any of the inactive ingredients in the drug product (refer to the IB for information on the clinical formulation).
  • Any other medical conditions (e.g., renal disease) that are not stable or controlled, or, which in the opinion of the Investigator, could affect the subject’s safety or interfere with the study assessments.


  • Any medications that, in the opinion of the Investigator, may contribute to cognitiven impairment, put the subject at higher risk for AEs, or impair the subject’s ability to perform cognitive testing or complete study procedures.
  • Use of allowed chronic medications at doses that have not been stable for at least 4 weeks prior to Screening Visit 1 and during Screening up to Study Day 1, or use of AD medications (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine) at doses that have not been stable for at least 8 weeks prior to Screening Visit 1 and during Screening up to Study Day 1.
  • Use of medications with platelet anti-aggregant or anti-coagulant properties (the use of aspirin at a prophylactic dose [≤325 mg daily] is allowed).
  • Use of illicit narcotic medication.
  • Vaccinations within 10 days prior to randomization (Day 1).
  • Participation in any active immunotherapy study targeting Aβ unless documentation of receipt of placebo is available.
  • Participation in any passive immunotherapy study targeting Aβ within 12 months of Screening unless documentation of receipt of placebo is available.
  • Participation in any study with purported disease-modifying effect in AD within 12 months prior to Screening unless documentation of receipt of placebo is available.
  • Subjects who developed ARIA-E during a previous disease-modifying trial should be excluded.
  • Participation in a previous study with aducanumab (subject is eligible if he/she did not receive active aducanumab).

Study Procedures

  • Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed).
  • Contraindication to having a PET scan (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any PET ligand or imaging agent, failure to participate in and comply with previous PET scans).
  • A negative PET scan result with any amyloid-targeting ligand within 6 months prior to Screening.
  • Have had or plan exposure to experimental radiation within 12 months prior to Screening such that radiodosimetry limits would be exceeded by participating in this study.
  • For subjects who consent to LP, any contraindications to having a LP (e.g., platelet count <100,000/μL, lumbar spine deformity). Any symptoms caused by or related to the optional LP during Screening must be resolved prior to randomization (Day 1). Subjects may still participate in the overall study even if participation in the optional LP portion is contraindicated.


  • Female subjects who are pregnant or currently breastfeeding.
  • Previous participation in this study. Subjects who fail Screening will be permitted to be rescreened once at the Sponsor’s discretion, except those who fail due to PET, MMSE, CDR global score >0.5, hepatitis B or C, or abnormal MRI findings. (Subjects who fail Screening due to a CDR global score of 0 may be rescreened; such subjects will be allowed to repeat the screening CDR assessment after 6 months.)
  • Subject currently living in an organized care facility with extensive intervention and/or support of daily living activities.
  • Blood donation (≥1 unit) within 1 month prior to Screening.
  • Inability to comply with study requirements.
  • Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the subject unsuitable for enrollment.

Inclusion Criteria for Long-Term Extension Period

To be eligible to participate in the LTE period, subjects must meet the following eligibility criteria at Week 78:

  • Subject must have completed the placebo-controlled period of the study including the Week 78 Visit. Subject must have taken at least 14 doses and not have missed more than 4 consecutive doses, except for subjects whose dose was suspended due to ARIA (See Section 7.2.1). Subjects who do not meet these criteria may enter the LTE period only with Sponsor’s approval.
  • The subject (or the subject’s legally authorized representative) has the ability to understand the purpose and risks of the study and provide signed and dated informed consent (or assent) and authorization to use confidential health information in accordance with national and local subject privacy regulations.
  • Female subjects of childbearing potential and male subjects must practice highly effective contraception during the study and for 24 weeks after their last dose of study treatment.
  • Apart from a clinical diagnosis of AD, the subject must be in good health as determined by the Investigator, based on medical history.
  • Must have the ability to comply with procedures for protocol-related tests.
  • Has one informant/care partner who, in the Investigator’s opinion, has frequent and sufficient contact with the subject as to be able to provide accurate information about the subject’s cognitive and functional abilities. The informant/care partner must minimally be available by phone to provide information to the Investigator and study staff about the subject and agrees to attend in person clinic visits that require partner input for scale completion. An informant/care partner should be available for the duration of the study, and the use of the same informant/care partner for the duration of the study is encouraged.

Exclusion Criteria for Long-Term Extension Period

Subjects will be excluded from entering the LTE period if at Week 78 they have:

  • Any medical or psychiatric contraindication or clinically significant abnormality that, in the opinion of the Investigator, will substantially increase the risk associated with the subject's participation in and completion of the study.


Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

David Knopman, M.D.

Closed for enrollment

More information


Publications are currently not available

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