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

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ClinicalTrials.gov Identifier: NCT01677572
Recruitment Status : Terminated (Study was discontinued based on futility analysis conducted on Phase 3 trials (NCT02477800 and NCT02484547) and not based on safety concerns.)
First Posted : September 3, 2012
Last Update Posted : August 3, 2020
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE August 30, 2012
First Posted Date  ICMJE September 3, 2012
Last Update Posted Date August 3, 2020
Actual Study Start Date  ICMJE October 5, 2012
Actual Primary Completion Date July 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 7, 2018)
Number of Participants with Adverse Events [ Time Frame: Baseline to week 518 ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 31, 2012)
Safety and tolerability as measured by adverse event monitoring, laboratory assessments, vital signs, neurological and physical exams, 12-lead ECG data, and brain MRI findings including the incidence of ARIA-E or ARIA-H [ Time Frame: Baseline to week 30 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2018)
  • Change from baseline in florbetapir-fluorine-18 (18F-AV-45F-AV-45) positron emission tomography (PET) imaging in certain brain areas. [ Time Frame: Day 1, Weeks 26, 54, End of year 2, 3, and 4 ]
  • Multiple dose pharmacokinetic (PK) serum concentrations of Aducanumab [ Time Frame: Up to week 518 ]
  • Change from Baseline in Incidence of Anti-Aducanumab Antibodies in Serum. [ Time Frame: Up to week 518 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2012)
  • Assess the effect of BIIB037 on cerebral amyloid plaque as measured by PET imaging [ Time Frame: Baseline to week 18 ]
  • Assess the multiple dose PK serum concentrations of BIIB037 [ Time Frame: Baseline to week 30 ]
  • Assess the immunogenecity of BIIB037 after multiple dose administration [ Time Frame: Baseline to week 30 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multiple Dose Study of Aducanumab (BIIB037) (Recombinant, Fully Human Anti-Aβ IgG1 mAb) in Participants With Prodromal or Mild Alzheimer's Disease
Official Title  ICMJE 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
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Alzheimer's Disease
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
  • 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.
    Intervention: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
  • 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.
    Interventions:
    • Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
    • Drug: Placebo
  • 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.
    Intervention: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
  • 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.
    Interventions:
    • Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
    • Drug: Placebo
  • 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.
    Intervention: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
  • 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.
    Interventions:
    • Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
    • Drug: Placebo
  • 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.
    Intervention: Drug: Aducanumab (recombinant, fully human anti-Aβ IgG1 mAb)
  • 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.
    Intervention: Drug: Placebo
Publications * Sevigny J, Chiao P, Bussière 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 Aβ plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323. Update in: Nature. 2017 Jun 21;546(7659):564.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 18, 2015)
197
Original Estimated Enrollment  ICMJE
 (submitted: August 31, 2012)
120
Actual Study Completion Date  ICMJE July 31, 2019
Actual Primary Completion Date July 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Australia,   Belgium
 
Administrative Information
NCT Number  ICMJE NCT01677572
Other Study ID Numbers  ICMJE 221AD103
2012-000349-10 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP