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Phase II Study of Florbetaben (BAY 94-9172) PET Imaging for Detection/Exclusion of Cerebral β-amyloid in Patients With Probable Alzheimer's Disease Compared to Healthy Volunteers

Primary Purpose

Alzheimer Disease, Amyloid Beta-Protein

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Florbetaben (BAY94-9172)
Sponsored by
Life Molecular Imaging SA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Alzheimer Disease focused on measuring Alzheimer Disease, Amyloid beta-Protein

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Each subject / Healthy volunteer (HV) who meets the following criteria will be eligible for enrollment into the study:

    • Is a man or woman and is > 55 of age, whereby females must be without childbearing potential (confirmed by either: age >/= 60; or history of hysterectomy, or last spontaneous bleeding at least 2 years prior to the study start)
    • Has at least 6 years of education
    • Is able to provide informed consent, understand the information provided on the purpose and conduct of the trial and to comply with study procedures
    • Possesses a general health that permits adequate compliance with all study procedures
    • The subject, or the subject and caregiver (for probable AD patients) will be compliant and have a high probability of completing the study
    • Informed consent has been signed and dated (with time) by the subject and/or the subject's caregiver (for probable AD patients)

  • Inclusion criteria for HV only:

    • Has no evidence of cognitive impairment
    • Has MRI brain scan that has been judged as "normal" (age- appropriate)

  • Inclusion criteria for patients with AD only:

    • Presents with positive assessment for dementia of Alzheimer's type
    • Does not fulfill the criteria Dementia with Lewy Bodies (DLB) or Vascular Dementia (VaD)
    • MRI brain scan findings that do not reveal changes indicative of stroke and/or generalized cerebrovascular disease
    • Has a caregiver that is willing and able to attend all study visits and perform the psychometric tests requiring the presence of a caregiver

Exclusion Criteria:

  • Has any contraindication to MRI examination scan
  • Is scheduled for surgery and/or another invasive procedure within the time period of up to 24 hours following IMP application
  • Is allergic to the IMP or any of its constituents and/or has a history of severe allergic reactions to drugs or allergens (e.g. patients / volunteers with allergic asthma)
  • is critically ill and/or medically unstable and whose clinical course during the observation period is unpredictable
  • Has a history of exposure to any radiation >15 milli Sieverts (mSv)/year (e.g. occupational or radiation therapy)
  • Is receiving drug therapy or other treatment that is known to lead to greatly fluctuating values of the hematological or chemical laboratory parameters or to severe side effects (e.g. chemotherapy)
  • 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 any radiopharmaceutical
  • Has a brain tumor or other intracranial lesion, a disturbance of cerebro-spinal fluid (CSF) circulation (e.g., normal pressure hydrocephalus) and/or a history of head trauma or brain surgery
  • Has an inflammatory or infectious central nervous system (CNS) disease, e.g. multiple sclerosis, HIV, syphilis, or Creutzfeldt-Jacob disease
  • Has a history, physical, laboratory or imaging findings indicative of a neurological or psychiatric illness
  • Has another disease that can cause disturbance of brain function (e.g. vitamin B12 or folic acid deficiency, disturbed thyroid function)
  • Has a history of alcohol or drug abuse
  • Has history of severe persistent depression

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Florbetaben (BAY94-9172)

Arm Description

Outcomes

Primary Outcome Measures

Specificity and Sensitivity of Florbetaben PET Scans Obtained in Part A Using Two Separate Algorithms and the Onsite Clinical Diagnosis as the Standard of Truth
Part A: For the calculation of sensitivity/specificity, a patient with probable AD was expected to have a positive florbetaben PET scan which was considered a match for sensitivity. A HV was expected to have a negative florbetaben PET scan which was considered a match for specificity. Standard of truth was the onsite clinical diagnosis. Two Beta-Amyloid Plaque Load (BAPL) algorithms for assessing the normality/abnormality of beta-amyloid plaque load in the brain scans were used. Using algorithm A (Majority Read), a brain scan of a subject with a BAPL score of "1" (without beta-amyloid plaque load) or "2" (with minor beta-amyloid plaque load) was considered normal and a BAPL score of "3" (with significant beta-amyloid plaque load) was considered abnormal. Using algorithm B (Average), a brain scan of a subject with a BAPL score of "1" was considered normal and a brain scan with a BAPL score of "2" or "3" was considered abnormal. Algorithm B was used in Part B and in the final
Specificity and Sensitivity of Florbetaben PET Scans Obtained in Part B Using Two Separate Algorithms and the Onsite Clinical Diagnosis as the Standard of Truth.
Part B: For the calculation of sensitivity/specificity, a patient with probable AD was expected to have a positive florbetaben PET scan, ie,abnormal scan (BAPL scores "2" or "3") which was considered a match for sensitivity. A HV was expected to have a negative florbetaben PET scan, ie,normal scan (BAPL score "1") which was considered a match for specificity. The clinical diagnosis was established by an independent consensus panel (CP) of experts in dementia. Two independent sets of PET data reads were performed. The first set was performed by a panel of three readers who received live, instructor-led training on the visual assessment procedure. The second set was performed by a panel of five separate readers who were trained on the visual assessment procedure with electronic media.

Secondary Outcome Measures

Sensitivity and Specificity for All Participants Using Two Additional Imaging Windows for the Visual Assessment
PET scans from two additional imaging windows (45-60 min and 110-130 min) were visually assessed
Kappa Coefficient as a Measure of Agreement Between Readers Concerning the Visual Assessment of Abnormality of the Brain Scan (Based on BAPL Score)
The agreement between 3 blinded readers concerning the visual assessment of abnormality of the brain scan (based on BAPL score) was measured by the kappa coefficient. Kappa values close to 1.0 indicate a high agreement while values close to 0 indicate random agreement.
Standard Uptake Value Ratios for Florbetaben Signal
The Standard Uptake Value Ratios for florbetaben signal in the frontal cortex, lateral temporal cortex, parietal cortex, anterior cingulate, posterior cingulate cortex, occipital cortex, and cerebellum (white matter) were determined as a quantitative measure of tracer uptake. The SUV is defined as the ratio of (1) the tissue radioactivity concentration c (in MBq/kg) at time point t, and (2) the injected activity (in MBq, extrapolated to the same time t) divided by the body weight (in kg). These SUV numbers from regions of interest were then used to derive SUV ratios (SUVR) using the SUV from the cerebellar cortex as reference.)

Full Information

First Posted
September 9, 2008
Last Updated
July 15, 2014
Sponsor
Life Molecular Imaging SA
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1. Study Identification

Unique Protocol Identification Number
NCT00750282
Brief Title
Phase II Study of Florbetaben (BAY 94-9172) PET Imaging for Detection/Exclusion of Cerebral β-amyloid in Patients With Probable Alzheimer's Disease Compared to Healthy Volunteers
Official Title
An Open-label, Non-randomized, Multi-center Study to Optimize Image Assessment and Evaluate the Efficacy and Safety of BAY 94-9172 (ZK 6013443) Positron Emission Tomography (PET) for Detection/Exclusion of Cerebral Amyloid Beta in Patients With Probable Alzheimer's Disease Compared to Healthy Volunteers
Study Type
Interventional

2. Study Status

Record Verification Date
July 2014
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
November 2010 (Actual)
Study Completion Date
November 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Life Molecular Imaging SA

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of this study is to evaluate the efficacy, safety of a single dose of BAY 94-9172 (ZK 6013443) as an investigational medicinal product (IMP) in detecting cerebral protein-plaque (amyloid beta) with positron emission tomography (PET). IMP binds to amyloidal beta protein accumulating in brain tissue already from early stages of Alzheimer's disease (AD). IMP is therefore a potential tracer to be used for detecting amyloid plaques. For each subject it is required to visit the study centre during the screening phase, on the PET imaging day and for 1 follow-up visit on the next day. A telephone call for safety follow-up will be performed 7 days after IMP administration. During the screening phase the subject's medical, neurological and surgical history, specific laboratory tests related to AD, MRI of the brain and certain neuro-psychiatric tests will be performed. Clinical safety measures (physical examinations, vital signs, electrocardiogram (ECG) and laboratory tests) will be performed on the PET imaging day before IMP injection and monitored during and after two PET imaging sessions. Clinical safety measures will be performed again on the follow-up visit next day. The results of PET imaging with IMP will be compared between probable AD patients and healthy volunteers (HV). The clinical diagnosis is based on international validated and accepted criteria and established after comprehensive clinical and neuro-psychiatric examinations

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease, Amyloid Beta-Protein
Keywords
Alzheimer Disease, Amyloid beta-Protein

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
422 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Florbetaben (BAY94-9172)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Florbetaben (BAY94-9172)
Intervention Description
Healthy volunteers and patients with probable Alzheimer's disease receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions
Primary Outcome Measure Information:
Title
Specificity and Sensitivity of Florbetaben PET Scans Obtained in Part A Using Two Separate Algorithms and the Onsite Clinical Diagnosis as the Standard of Truth
Description
Part A: For the calculation of sensitivity/specificity, a patient with probable AD was expected to have a positive florbetaben PET scan which was considered a match for sensitivity. A HV was expected to have a negative florbetaben PET scan which was considered a match for specificity. Standard of truth was the onsite clinical diagnosis. Two Beta-Amyloid Plaque Load (BAPL) algorithms for assessing the normality/abnormality of beta-amyloid plaque load in the brain scans were used. Using algorithm A (Majority Read), a brain scan of a subject with a BAPL score of "1" (without beta-amyloid plaque load) or "2" (with minor beta-amyloid plaque load) was considered normal and a BAPL score of "3" (with significant beta-amyloid plaque load) was considered abnormal. Using algorithm B (Average), a brain scan of a subject with a BAPL score of "1" was considered normal and a brain scan with a BAPL score of "2" or "3" was considered abnormal. Algorithm B was used in Part B and in the final
Time Frame
90 - 110 min after investigational medical product (IMP) injection
Title
Specificity and Sensitivity of Florbetaben PET Scans Obtained in Part B Using Two Separate Algorithms and the Onsite Clinical Diagnosis as the Standard of Truth.
Description
Part B: For the calculation of sensitivity/specificity, a patient with probable AD was expected to have a positive florbetaben PET scan, ie,abnormal scan (BAPL scores "2" or "3") which was considered a match for sensitivity. A HV was expected to have a negative florbetaben PET scan, ie,normal scan (BAPL score "1") which was considered a match for specificity. The clinical diagnosis was established by an independent consensus panel (CP) of experts in dementia. Two independent sets of PET data reads were performed. The first set was performed by a panel of three readers who received live, instructor-led training on the visual assessment procedure. The second set was performed by a panel of five separate readers who were trained on the visual assessment procedure with electronic media.
Time Frame
90 - 110 min after IMP injection
Secondary Outcome Measure Information:
Title
Sensitivity and Specificity for All Participants Using Two Additional Imaging Windows for the Visual Assessment
Description
PET scans from two additional imaging windows (45-60 min and 110-130 min) were visually assessed
Time Frame
45 - 60 min and 110 - 130 min after IMP injection
Title
Kappa Coefficient as a Measure of Agreement Between Readers Concerning the Visual Assessment of Abnormality of the Brain Scan (Based on BAPL Score)
Description
The agreement between 3 blinded readers concerning the visual assessment of abnormality of the brain scan (based on BAPL score) was measured by the kappa coefficient. Kappa values close to 1.0 indicate a high agreement while values close to 0 indicate random agreement.
Time Frame
45-60 min, 90-110 min, 110-130 min
Title
Standard Uptake Value Ratios for Florbetaben Signal
Description
The Standard Uptake Value Ratios for florbetaben signal in the frontal cortex, lateral temporal cortex, parietal cortex, anterior cingulate, posterior cingulate cortex, occipital cortex, and cerebellum (white matter) were determined as a quantitative measure of tracer uptake. The SUV is defined as the ratio of (1) the tissue radioactivity concentration c (in MBq/kg) at time point t, and (2) the injected activity (in MBq, extrapolated to the same time t) divided by the body weight (in kg). These SUV numbers from regions of interest were then used to derive SUV ratios (SUVR) using the SUV from the cerebellar cortex as reference.)
Time Frame
90-110 min post injection

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Each subject / Healthy volunteer (HV) who meets the following criteria will be eligible for enrollment into the study: Is a man or woman and is > 55 of age, whereby females must be without childbearing potential (confirmed by either: age >/= 60; or history of hysterectomy, or last spontaneous bleeding at least 2 years prior to the study start) Has at least 6 years of education Is able to provide informed consent, understand the information provided on the purpose and conduct of the trial and to comply with study procedures Possesses a general health that permits adequate compliance with all study procedures The subject, or the subject and caregiver (for probable AD patients) will be compliant and have a high probability of completing the study Informed consent has been signed and dated (with time) by the subject and/or the subject's caregiver (for probable AD patients) Inclusion criteria for HV only: Has no evidence of cognitive impairment Has MRI brain scan that has been judged as "normal" (age- appropriate) Inclusion criteria for patients with AD only: Presents with positive assessment for dementia of Alzheimer's type Does not fulfill the criteria Dementia with Lewy Bodies (DLB) or Vascular Dementia (VaD) MRI brain scan findings that do not reveal changes indicative of stroke and/or generalized cerebrovascular disease Has a caregiver that is willing and able to attend all study visits and perform the psychometric tests requiring the presence of a caregiver Exclusion Criteria: Has any contraindication to MRI examination scan Is scheduled for surgery and/or another invasive procedure within the time period of up to 24 hours following IMP application Is allergic to the IMP or any of its constituents and/or has a history of severe allergic reactions to drugs or allergens (e.g. patients / volunteers with allergic asthma) is critically ill and/or medically unstable and whose clinical course during the observation period is unpredictable Has a history of exposure to any radiation >15 milli Sieverts (mSv)/year (e.g. occupational or radiation therapy) Is receiving drug therapy or other treatment that is known to lead to greatly fluctuating values of the hematological or chemical laboratory parameters or to severe side effects (e.g. chemotherapy) 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 any radiopharmaceutical Has a brain tumor or other intracranial lesion, a disturbance of cerebro-spinal fluid (CSF) circulation (e.g., normal pressure hydrocephalus) and/or a history of head trauma or brain surgery Has an inflammatory or infectious central nervous system (CNS) disease, e.g. multiple sclerosis, HIV, syphilis, or Creutzfeldt-Jacob disease Has a history, physical, laboratory or imaging findings indicative of a neurological or psychiatric illness Has another disease that can cause disturbance of brain function (e.g. vitamin B12 or folic acid deficiency, disturbed thyroid function) Has a history of alcohol or drug abuse Has history of severe persistent depression
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
Sun City
State/Province
Arizona
ZIP/Postal Code
85351
Country
United States
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02906
Country
United States
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
City
Erlangen
State/Province
Bayern
ZIP/Postal Code
91054
Country
Germany
City
München
State/Province
Bayern
ZIP/Postal Code
81377
Country
Germany
City
München
State/Province
Bayern
ZIP/Postal Code
81675
Country
Germany
City
Essen
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
45122
Country
Germany
City
Jülich
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
52425
Country
Germany
City
Münster
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
48149
Country
Germany
City
Dresden
State/Province
Sachsen
ZIP/Postal Code
01307
Country
Germany
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
City
Berlin
ZIP/Postal Code
13125
Country
Germany
City
Kobe
State/Province
Hyogo
ZIP/Postal Code
650-0017
Country
Japan
City
Kobe
State/Province
Hyogo
ZIP/Postal Code
650-0047
Country
Japan
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8603
Country
Japan
City
Zürich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
21481640
Citation
Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, Buerger K, Hiemeyer F, Wittemer-Rump SM, Seibyl J, Reininger C, Sabri O; Florbetaben Study Group. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 2011 May;10(5):424-35. doi: 10.1016/S1474-4422(11)70077-1. Epub 2011 Apr 8.
Results Reference
result
PubMed Identifier
33773598
Citation
Bullich S, Roe-Vellve N, Marquie M, Landau SM, Barthel H, Villemagne VL, Sanabria A, Tartari JP, Sotolongo-Grau O, Dore V, Koglin N, Muller A, Perrotin A, Jovalekic A, De Santi S, Tarraga L, Stephens AW, Rowe CC, Sabri O, Seibyl JP, Boada M. Early detection of amyloid load using 18F-florbetaben PET. Alzheimers Res Ther. 2021 Mar 27;13(1):67. doi: 10.1186/s13195-021-00807-6.
Results Reference
derived

Learn more about this trial

Phase II Study of Florbetaben (BAY 94-9172) PET Imaging for Detection/Exclusion of Cerebral β-amyloid in Patients With Probable Alzheimer's Disease Compared to Healthy Volunteers

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