Multiple Dose Study of Aducanumab (BIIB037) (Recombinant, Fully Human Anti-Aβ IgG1 mAb) in Participants With Prodromal or Mild Alzheimer's Disease (PRIME)

A Randomized, Double-Blinded, Placebo-Controlled Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB037 in Subjects With Prodromal or Mild Alzheimer's Disease

The primary objective of this study is to evaluate the safety and tolerability of multiple doses of Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb) in participants with prodromal or mild Alzheimer's Disease (AD). The secondary objectives of this study are to assess the effect on cerebral amyloid plaque content as measured by florbetapir-fluorine-18 (18F-AV-45F-AV-45) positron emission tomography (PET) imaging, to assess the multiple dose serum concentrations of Aducanumab and to evaluate the immunogenicity of Aducanumab after multiple dose administration in this population.

Study Overview

• Status: Terminated
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Drug: Placebo

Detailed Description

The study consists of a placebo-controlled period to study week 54, followed by a long-term extension to study week 518. The placebo-controlled period is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel, 2 additional treatment arms beginning in parallel, and the last 2 treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period for up to 42 additional doses of active drug for the first 3 years of LTE. Furthermore, up until the last participant in Arms 8 and 9 has had his or her last dose in the fifth year of the LTE, eligible participants will be able to continue treatment beyond the third year of the LTE.

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • NNS Clinical Research, LLC
  • California
    • Laguna Hills, California, United States, 92653
      • Senior Clinical Trials, Inc.
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute, Inc.
    • Long Beach, California, United States, 90806
      • Collaborative Neuroscience Network, LLC
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Oxnard, California, United States, 93030
      • Pacific Neuroscience Medical Group
    • San Diego, California, United States, 92103
      • Pacific Research Network, Inc.
    • San Francisco, California, United States, 94109
      • San Francisco Clinical Research Center
    • Stanford, California, United States, 94304
      • Stanford University Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Alzheimer's Disease Research Unit, Yale University
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Georgetown University Hospital
  • Florida
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research, Inc.
    • Fort Myers, Florida, United States, 33912
      • Neuropsychiatric Research Center of Southwest Florida
    • Hallandale Beach, Florida, United States, 33009
      • MD Clinical Trials, Inc.
    • Miami, Florida, United States, 33137
      • Miami Jewish Health Systems
    • Miami Springs, Florida, United States, 33166
      • Galiz Research, LLC
    • Orlando, Florida, United States, 32806
      • Compass Research, LLC
    • Sunrise, Florida, United States, 33351
      • Infinity Clinical Research, Inc.
    • Tampa, Florida, United States, 33609
      • Axiom Clinical Research of Florida
    • Tampa, Florida, United States, 33613
      • Stedman Clinical Trials, LLC
  • Georgia
    • Decatur, Georgia, United States, 30033
      • NeuroStudies.net, LLC
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neurosciences Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63118
      • St. Louis Clinical Trials, LLC
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
    • Marlton, New Jersey, United States, 08053
      • CRI Lifetree
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute of NJ
  • New York
    • Latham, New York, United States, 12110
      • Empire Neurology, PC
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Insight Clinical Trials Llc
  • Oregon
    • Portland, Oregon, United States, 97210
      • Summit Research Network (Oregon) Inc.
  • Rhode Island
    • East Providence, Rhode Island, United States, 02906
      • Brown Hospital
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Participants must be ambulatory.
• Participants must meet the following core clinical criteria as determined by the Investigator:

Prodromal Alzheimer's Disease (AD) (all of the criteria must apply):

• Mini Mental State Examination (MMSE) scores between 24-30 (inclusive)
• a spontaneous memory complaint
• objective memory loss defined as a free recall score of ≤27 on the Free and Cued Selective Reminding Test (FCSRT)
• a global Clinical Dementia Rating Scale (CDR) score of 0.5
• absence of significant levels of impairment in other cognitive domains
• essentially preserved activities of daily living, and an absence of dementia. OR

Mild Alzheimer's Disease (AD) criteria (all criteria must apply):

• Mini Mental State Examination (MMSE) scores between 20-26 (inclusive)
• a global Clinical Dementia Rating Scale (CDR) of 0.5 or 1.0
• meeting the National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD.
• Participants must have a positive florbetapir positron emission tomography (PET) amyloid scan.
• Participants must consent to apolipoprotein E (ApoE) genotyping.
• Apart from clinical diagnosis of Alzheimer's Disease (AD), participant must be in good health.
• 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 participant's cognitive impairment.
• Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year.
• Clinically significant psychiatric illness in past 6 months.
• Seizure in the past 3 years.
• Poorly controlled diabetes mellitus.
• History of unstable angina, myocardial infarction, chronic heart failure, or clinical 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.
• Brain MRI showing evidence of acute or sub-acute micro or macrohemorrhage, greater than 4 microhemorrhages, cortical infarct or greater than one 1 lunar infarct.
• Any contraindications to brain MRI or positron emission tomography (PET) scans.
• Negative positron emission tomography (PET) scan with any amyloid-targeting ligand within 48 weeks of Screening.
• Clinically significant 12-lead electrocardiogram (ECG) abnormalities.
• Alcohol or substance abuse in past 1 year.
• Taking blood thinners (except for aspirin at a prophylactic dose or less)
• Have changes in medications or doses of medication in past 4 weeks.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose #1 Aducanumab; Intravenous doses of low-dose level #1 Aducanumab administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human
Experimental: Low-dose #2 Aducanumab; Intravenous doses of low-dose level #2 Aducanumab administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human
Placebo Comparator: Placebo (low dose group); Intravenous doses of placebo administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human; Drug: Placebo; Placebo to mimic the low dose, mid-dose and high-dose treatment arms of the experimental intervention; administered by intravenous (IV) infusion on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.
Experimental: Mid-dose Aducanumab; Intravenous doses of mid-dose Aducanumab administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human
Placebo Comparator: Placebo (mid dose group); Intravenous doses of placebo administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human; Drug: Placebo; Placebo to mimic the low dose, mid-dose and high-dose treatment arms of the experimental intervention; administered by intravenous (IV) infusion on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.
Experimental: High-dose Aducanumab; Intravenous doses of high-dose Aducanumab administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human
Placebo Comparator: Placebo (high dose group); Intravenous doses of placebo administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose administered approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human; Drug: Placebo; Placebo to mimic the low dose, mid-dose and high-dose treatment arms of the experimental intervention; administered by intravenous (IV) infusion on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.
Experimental: Aducanumab Titration; Intravenous doses of Aducanumab administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose approximately 4 weeks apart for up to an additional 112 doses.	Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb); Participants will receive an infusion of Aducanumab on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic and assigned does levels. The infusion will be administered for approximately 1 hour. The study is conducted with a staggered, parallel group design, with the first 3 treatment arms conducted in parallel, 2 further treatment arms subsequently beginning in parallel and the 2 last treatment arms subsequently beginning in parallel. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.; Other Names: IgG1; anti-A* mAb; Fully human
Placebo Comparator: Placebo (Titration Group); Intravenous doses of placebo administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Qualifying participants can continue into the long-term extension at a dose approximately 4 weeks apart for up to an additional 112 doses.	Drug: Placebo; Placebo to mimic the low dose, mid-dose and high-dose treatment arms of the experimental intervention; administered by intravenous (IV) infusion on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, and 365 (±2 days) at the study clinic. Qualifying participants can enter the long-term extension period at doses described in the treatment arms for up to an additional 112 doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Adverse Events	Baseline to week 518

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in florbetapir-fluorine-18 (18F-AV-45F-AV-45) positron emission tomography (PET) imaging in certain brain areas.	Day 1, Weeks 26, 54, End of year 2, 3, and 4
Multiple dose pharmacokinetic (PK) serum concentrations of Aducanumab	Up to week 518
Change from Baseline in Incidence of Anti-Aducanumab Antibodies in Serum.	Up to week 518

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323.

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2012
• Primary Completion (Actual): July 31, 2019
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: August 30, 2012
• First Submitted That Met QC Criteria: August 31, 2012
• First Posted (Estimate): September 3, 2012

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 31, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: BIIB037; Aducanumab
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulin G
• Other Study ID Numbers: 221AD103; 2012-000349-10 (EudraCT Number)