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

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

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

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Florbetaben (BAY94-9172)

• Study Type: Interventional
• Enrollment (Actual): 218
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Florbetaben (BAY94-9172)	Drug: Florbetaben (BAY94-9172); Single intravenous injection 1-5ml, 300 MBq (+/- 20%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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".	90-110 minutes post injection (PET image acquisition)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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".	90-110 minutes post injection (PET image acquisition)
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).	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".	90-110 minutes post injection (PET image acquisition)
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).	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".	90-110 minutes post injection (PET image acquisition)
Sensitivity and Specificity of the Subject Level Composite SUVR Calculated Based on Pathology Results.	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.	90-110 minutes post injection (PET image acquisition)
Subject Level Composite SUVRs by SOT for Baseline and Available Follow-Up Scans	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.	90-110 minutes post injection (PET image acquisition)

Collaborators and Investigators

• Sponsor: Life Molecular Imaging SA
• Investigators: Study Director: Piramal Imaging SA Study Director, Life Molecular Imaging SA

Publications and helpful links

General Publications

• Seibyl J, Catafau AM, Barthel H, Ishii K, Rowe CC, Leverenz JB, Ghetti B, Ironside JW, Takao M, Akatsu H, Murayama S, Bullich S, Mueller A, Koglin N, Schulz-Schaeffer WJ, Hoffmann A, Sabbagh MN, Stephens AW, Sabri O. Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study. J Nucl Med. 2016 Jun;57(6):900-6. doi: 10.2967/jnumed.115.161927. Epub 2016 Jan 28.
• Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, Senda K, Murayama S, Ishii K, Takao M, Beach TG, Rowe CC, Leverenz JB, Ghetti B, Ironside JW, Catafau AM, Stephens AW, Mueller A, Koglin N, Hoffmann A, Roth K, Reininger C, Schulz-Schaeffer WJ; Florbetaben Phase 3 Study Group. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study. Alzheimers Dement. 2015 Aug;11(8):964-74. doi: 10.1016/j.jalz.2015.02.004. Epub 2015 Mar 28.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: November 16, 2009
• First Submitted That Met QC Criteria: November 25, 2009
• First Posted (Estimate): November 26, 2009

Study Record Updates

• Last Update Posted (Estimate): May 27, 2016
• Last Update Submitted That Met QC Criteria: April 27, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Amyloid beta-protein; Florbetaben
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 14595; 2009-012569-79 (EudraCT Number)