Phase III Study of Florbetaben (BAY94-9172) PET Imaging for Detection/Exclusion of Cerebral β-amyloid Compared to Histopathology

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Piramal Imaging SA
ClinicalTrials.gov Identifier:
NCT01020838
First received: November 16, 2009
Last updated: March 13, 2015
Last verified: March 2015
  Purpose

To determine the sensitivity and specificity of the visual assessment of tracer uptake in the Florbetaben PET images compared to histological verification of the presence or absence of cerebral β-amyloid in the respective histopathologic post mortem specimens as the standard of truth


Condition Intervention Phase
Alzheimer Disease
Drug: Florbetaben (BAY94-9172)
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: An Open-label, Non-randomized Study to Evaluate the Efficacy and Safety of BAY94-9172 (ZK 6013443) Positron Emission Tomography (PET) Imaging for Detection/Exclusion of Cerebral Beta-amyloid When Compared to Postmortem Histopathology

Resource links provided by NLM:


Further study details as provided by Piramal Imaging SA:

Primary Outcome Measures:
  • Sensitivity and Specificity of the Majority Read of Visual Assessment of Tracer Uptake Compared to Histological Verification of the Presence or Absence of Cerebral Beta-amyloid in Postmortem Specimens [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]
    The sensitivity/specificity of the visual assessment were calculated based on the majority read assessment of regional tracer uptake. This result was derived from assessments by 3 independent readers for brain regions of a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was a centralized histopathological determination of β-amyloid presence/absence based on both Bielschowsky silver and immunohistochemical staining. Based on the PET images, a brain region was classified as "normal" or "abnormal" depending on the presence or absence of regional tracer uptake in the respective region. "Normal" therefore meant absence of β-amyloid and "abnormal" presence of β-amyloid. Sensitivity was defined as the percentage of abnormal brain regions from all regions where an SOT was available and the SOT was "β-amyloid present". Specificity was defined as the percentage of normal brain regions from all regions where an SOT was available and was "β-amyloid not present".


Secondary Outcome Measures:
  • Sensitivity and Specificity of the Majority Read "Whole Brain" Visual Assessment in Detecting/Excluding Cerebral Neuritic β-amyloid Plaques Compared With the Histopathological Verification With Bielschowsky Silver Staining (SOT 1). [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]

    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a centralized histopathological assessment of the presence/absence of β-amyloid based on Bielschowsky silver staining (SOT 1).

    The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".


  • Sensitivity and Specificity of the Majority Read "Whole Brain" Visual Assessment in Detecting/Excluding Cerebral Neuritic β-amyloid Plaques Compared With Histopathological Verification With Bielschowsky Silver Staining and Immunohistochemistry (SOT 2). [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]

    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a centralized histopathological assessment of the presence/absence of β-amyloid based on Bielschowsky silver staining and immunohistochemistry (SOT 2).

    The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".


  • Sensitivity and Specificity of the Majority Read "Whole Brain" Visual Assessment in Detecting/Excluding Cerebral Neuritic β-amyloid Plaques Compared With the Histopathological Verification According to CERAD Criteria (SOT 3). [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]

    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a histopathological assessment of the presence/absence of β-amyloid according to CERAD Criteria (SOT 3).

    The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".


  • Sensitivity and Specificity of the Subject Level Composite SUVR Calculated Based on Pathology Results. [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]
    Sensitivity and specificity of subject level composite Standard Uptake Value Ratios (SUVR) by SOT for subjects with available brain tissue and 10 healthy volunteers. The SUVR were determined as a quantitative measure of tracer uptake. The SUV is defined as the ratio of the tissue radioactivity concentration c (in MBq/kg) at time point t, and the injected activity (in MBq), extrapolated to the same time (t) divided by the body weight (in kg). SUV numbers were then used to derive SUV ratios (SUVR) using the SUV from the cerebellar cortex as reference. SOTs comprised Bielschowsky silver staining (SOT 1), Bielschowsky silver staining with immunohistochemistry (SOT 2) and neuropathology assessment according to CERAD (SOT 3). SUVR analysis was performed for baseline and available follow-up scans. The optimal threshold for the distinction between β-amyloid present yes/no according to the respective SOT was derived based on ROC curve analyses and used to calculate sensitivity and specificity.

  • Subject Level Composite SUVRs by SOT for Baseline and Available Follow-Up Scans [ Time Frame: 90-110 minutes post injection (PET image acquisition) ] [ Designated as safety issue: No ]
    Subject level composite SUVRs (calculated as mean of SUVRs from the frontal, parietal, lateral temporal, anterior and posterior cingulate, and occipital cortices) by SOT are reported for subjects with available brain tissue. The initial drug administration group includes additionally 10 healthy controls who were considered as ß-amyloid negative. The SOTs for deceased subjects were based on Bielschowsky silver staining (SOT 1), Bielschowsky silver staining in combination with immunohistochemistry (SOT 2) and neuropathology assessment according to CERAD (SOT 3). SUVR analysis was performed for baseline and available follow-up scans.


Enrollment: 218
Study Start Date: November 2009
Study Completion Date: May 2014
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Florbetaben (BAY94-9172) Drug: Florbetaben (BAY94-9172)
Single intravenous injection 1-5ml, 300 MBq (+/- 20%)

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females, no child-bearing potential or negative urine pregnancy test on day of BAY94-9172 injection
  • Exhibits visual, auditory, and communicative capabilities adequate to provide informed consent or assent and comply with study procedures
  • Is willing and able to lie down in magnetic resonance imaging (MRI) and positron emission tomography (PET) scanners
  • Is willing to donate their brain for postmortem examination in case of death
  • The subject, or the subject and/or legally acceptable representative will be compliant and have a high probability of completing the study in the opinion of the investigator
  • Has been fully informed about the study, including provisions of the Health Insurance Portability and Accountability Act (HIPAA), as applicable, and informed consent or assent has been signed and dated (with time) by the subject and/or the subject's legally acceptable representative
  • The subjects who have participated in a previous florbetaben study e.g. study 311741 may be included in the present study. The MRI- and florbetaben PET scan do not need to be repeated if both scans were performed within twelve months prior to inclusion.

Exclusion Criteria:

  • Has severe cerebral macrovascular (ie, multi-stroke) disease or brain tumor (metastasis/brain cancer) as verified by MRI
  • Has any contraindication to magnetic resonance imaging (MRI) examination, eg, metal implants or phobia as determined by the onsite radiologist performing the scan
  • Has been previously enrolled in this study or participated in a clinical study involving an investigational pharmaceutical product within 30 days prior to screening and/or was administered a radiopharmaceutical within 10 radioactive half-lives prior to study drug administration in this study
  • Has severe cardio-vascular instability requiring intensive care surveillance and/or therapeutic intervention (i.e. catecholamine infusion)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01020838

Locations
United States, Arizona
Sun City, Arizona, United States, 85351
United States, California
Stanford, California, United States, 94305
United States, Florida
Tampa, Florida, United States, 33616
United States, New Jersey
Teaneck, New Jersey, United States, 07666
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Dallas, Texas, United States, 75390
Houston, Texas, United States, 77030
San Antonio, Texas, United States, 78229
Australia, Victoria
Heidelberg, Victoria, Australia, 3084
France
Lille, France, 59037
Strasbourg, France, 67091
Germany
Jülich, Nordrhein-Westfalen, Germany, 52425
Leipzig, Sachsen, Germany, 04103
Japan
Toyohashi, Aichi, Japan, 441-8124
Toyohashi, Aichi, Japan, 441-8021
Toyohashi, Aichi, Japan, 440-0045
Isezaki, Gunma, Japan, 372-0006
Hamamatsu, Shizuoka, Japan, 432-8580
Itabashi-ku, Tokyo, Japan, 173-0015
Sponsors and Collaborators
Piramal Imaging SA
Investigators
Study Director: Piramal Imaging SA Study Director Piramal Imaging SA
  More Information

Additional Information:
No publications provided

Responsible Party: Piramal Imaging SA
ClinicalTrials.gov Identifier: NCT01020838     History of Changes
Other Study ID Numbers: 14595, 2009-012569-79
Study First Received: November 16, 2009
Results First Received: February 2, 2015
Last Updated: March 13, 2015
Health Authority: Australia: Human Research Ethics Committee
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Japan: Pharmaceuticals and Medical Devices Agency
United States: Food and Drug Administration

Keywords provided by Piramal Imaging SA:
Florbetaben
Amyloid beta-protein
Alzheimer's disease

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Dementia
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies

ClinicalTrials.gov processed this record on March 30, 2015