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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

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ClinicalTrials.gov Identifier: NCT00750282
Recruitment Status : Completed
First Posted : September 10, 2008
Results First Posted : July 16, 2014
Last Update Posted : July 24, 2014
Sponsor:
Information provided by (Responsible Party):
Life Molecular Imaging SA

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Diagnostic
Conditions Alzheimer Disease
Amyloid Beta-Protein
Intervention Drug: Florbetaben (BAY94-9172)
Enrollment 422
Recruitment Details

There were two parts in this study, Part A and Part B. Part A was conducted in Australia, Germany, Switzerland and USA. Subjects were recruited from 17 centers. HVs were age matched to subjects with probable Alzheimer's (AD).

Part B was conducted in Australia, Germany, Japan, Switzerland, and USA, subjects recruited from 22 centers.

Pre-assignment Details

Part A screened 214 subjects; 113 AD and 101 HV. There were 63 screen failures (40 for inclusion criteria, 14 withdrew consent, 9 for other reasons) and one dropout prior to receiving study drug.

Part B screened 392 subjects; 204 AD and 188 HV. There were 118 screen failures for similar reasons and 2 dropouts prior to receiving study drug.

Arm/Group Title Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients
Hide Arm/Group Description Florbetaben (BAY94-9172) : Healthy volunteers receiving 300 megabequerel (MBq) single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions. Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving 300 MBq single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Healthy volunteers receiving 300 MBq single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving 300 MBq single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions
Period Title: Overall Study
Started 69 82 126 148
Completed 69 81 125 147
Not Completed 0 1 1 1
Arm/Group Title Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients Total
Hide Arm/Group Description Florbetaben (BAY94-9172) : Healthy volunteers receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving 300 MBq single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Healthy volunteers receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving 300 MBq single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Total of all reporting groups
Overall Number of Baseline Participants 69 81 125 147 422
Hide Baseline Analysis Population Description
dropout in Part A occurred due to pre-treatment AEs. dropouts in Part B occurred due to withdrawal of consent.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 81 participants 125 participants 147 participants 422 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
23
  33.3%
19
  23.5%
21
  16.8%
15
  10.2%
78
  18.5%
>=65 years
46
  66.7%
62
  76.5%
104
  83.2%
132
  89.8%
344
  81.5%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 69 participants 81 participants 125 participants 147 participants 422 participants
68.2  (6.86) 70.7  (7.82) 70.7  (6.30) 73.9  (7.30) 71.4  (7.36)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 81 participants 125 participants 147 participants 422 participants
Female
39
  56.5%
36
  44.4%
52
  41.6%
73
  49.7%
200
  47.4%
Male
30
  43.5%
45
  55.6%
73
  58.4%
74
  50.3%
222
  52.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 69 participants 81 participants 125 participants 147 participants 422 participants
United States 8 3 22 31 64
Australia 9 6 11 5 31
Germany 49 71 63 72 255
Switzerland 3 1 0 11 15
Japan 0 0 29 28 57
1.Primary Outcome
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had PET imaging data and did not have a major protocol violation were included in the analysis.(n=146)
Arm/Group Title AD (Sensitivity) Group HV (Specificity) Group
Hide Arm/Group Description:
All evaluated subjects with Alzheimer's disease
All evaluated healthy volunteers
Overall Number of Participants Analyzed 78 68
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of subjects
Majority Read Sens/ Spec (BAPL2 = abnormal)
79.49
(70.47 to 88.51)
91.18
(84.38 to 97.97)
Average Sens / Spec (BAPL2 = normal)
74.79
(65.69 to 83.88)
96.08
(91.85 to 100.30)
2.Primary Outcome
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.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had PET imaging data and did not have a major protocol violation were included in the analysis
Arm/Group Title AD (Sensitivity) Group HV (Specificity) Group
Hide Arm/Group Description:
All subjects evaluated as probable AD by consensus panel
All subjects evaluated as healthy volunteer by consensus panel
Overall Number of Participants Analyzed 116 118
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of subjects
Sens / Spec (average 3 readers)
67.24
(58.70 to 75.78)
96.61
(93.34 to 99.88)
Sens / Spec (additional read, median 5 readers)
78.5
(71.0 to 85.9)
89.2
(83.6 to 94.7)
3.Secondary Outcome
Title Sensitivity and Specificity for All Participants Using Two Additional Imaging Windows for the Visual Assessment
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had PET imaging data and did not have a major protocol violation were included in the analysis
Arm/Group Title AD (Sensitivity) Group (Part A) HV (Specificity) Group (Part A) AD (Sensitivity) Group (Part B) HV (Specificity) Group (Part B)
Hide Arm/Group Description:
All evaluated subjects with Alzheimer's disease from Part A
All evaluated healthy volunteers from Part A
All evaluated subjects with probable Alzheimer's disease from part B
All evaluated healthy volunteers from Part B
Overall Number of Participants Analyzed 78 68 116 118
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of subjects
Sensitivity & Specificity (45-60 min)
73.93
(64.88 to 82.98)
94.61
(90.36 to 98.85)
71.55
(63.34 to 79.76)
94.07
(89.81 to 96.55)
Sensitivity & Specificity (110-130 min)
70.56
(60.98 to 80.15)
98.01
(95.65 to 100.37)
73.04
(64.93 to 81.15)
96.58
(93.29 to 99.87)
4.Secondary Outcome
Title Kappa Coefficient as a Measure of Agreement Between Readers Concerning the Visual Assessment of Abnormality of the Brain Scan (Based on BAPL Score)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had PET imaging data and did not have a major protocol violation were included in the analysis
Arm/Group Title Imaging Window 45-60 Min Part A Imaging Window 90-110 Min Part A Imaging Window 110-130 Min Part A Imaging Window 45-60 Min Part B Imaging Window 90-110 Min Part B Imaging Window 110-130 Min Part B
Hide Arm/Group Description:
Kappa coefficient estimate for PET data collected 45-60 min post-injection in Part A
Kappa coefficient estimate for PET data collected 90-110 min post-injection in Part A
Kappa coefficient estimate for PET data collected 110-130 min post-injection in Part A.
Kappa coefficient estimate for PET data collected 45-60 min post-injection in Part B
Kappa coefficient estimate for PET data collected 90-110 min post-injection in Part B
Kappa coefficient estimate for PET data collected 110-130 min post-injection in Part B.
Overall Number of Participants Analyzed 150 150 150 272 272 272
Measure Type: Number
Unit of Measure: Kappa coefficient
0.56 0.60 0.67 0.78 0.86 0.86
5.Secondary Outcome
Title Standard Uptake Value Ratios for Florbetaben Signal
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had PET imaging data and did not have a major protocol violation were included in the analysis
Arm/Group Title Alzheimer's (AD) Group (Part A) Healthy Volunteer (HV) Group (Part A) Alzheimer's (AD) Group (Part B) Healthy Volunteer (HV) Group (Part B)
Hide Arm/Group Description:
All evaluated subjects with Alzheimer's disease
All evaluated healthy volunteers
All subjects with consensus panel based diagnosis of "probable AD"
All subjects that were confirmed by consensus panel as healthy volunteers
Overall Number of Participants Analyzed 78 68 116 118
Mean (Standard Deviation)
Unit of Measure: ratio
Frontal cortex 1.608  (0.3207) 1.295  (0.1151) 1.646  (0.2905) 1.301  (0.1961)
Lateral temporal cortex 1.571  (0.2881) 1.259  (0.1058) 1.619  (0.2787) 1.292  (0.1620)
Parietal cortex 1.528  (0.2896) 1.234  (0.1161) 1.602  (0.2705) 1.267  (0.1709)
Anterior cingulate 1.723  (0.3522) 1.397  (0.1425) 1.786  (0.3145) 1.434  (0.2387)
Posterior cingulate cortex 1.795  (0.3149) 1.422  (0.1565) 1.852  (0.3187) 1.493  (0.2351)
Occipital cortex 1.495  (0.2203) 1.309  (0.0864) 1.560  (0.2460) 1.341  (0.1281)
Composite SUVR 1.620  (0.29) 1.320  (0.11) 1.678  (0.2699) 1.355  (0.1784)
Time Frame A maximum of 64 days. Up to 56 days during the screening process and 8 days from baseline to second follow-up visit.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients
Hide Arm/Group Description Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Healthy volunteers receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Patients with probable Alzheimer's disease receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions Florbetaben (BAY94-9172) : Healthy volunteers receiving single injection of investigational medicinal product BAY 94-9172 followed by subsequent PET imaging sessions
All-Cause Mortality
Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/69 (1.45%)      1/81 (1.23%)      2/125 (1.60%)      0/147 (0.00%)    
Cardiac disorders         
Arrhythmia  1  0/69 (0.00%)  0 1/81 (1.23%)  1 1/125 (0.80%)  2 0/147 (0.00%)  0
General disorders         
Chest pain  1  0/69 (0.00%)  0 1/81 (1.23%)  2 0/125 (0.00%)  0 0/147 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Clear cell endometrial carcinoma  1  0/69 (0.00%)  0 0/81 (0.00%)  0 1/125 (0.80%)  1 0/147 (0.00%)  0
Nervous system disorders         
Syncope  1  1/69 (1.45%)  1 0/81 (0.00%)  0 0/125 (0.00%)  0 0/147 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (13.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Part A Healthy Volunteers Part A Alzheimer Patients Part B Healthy Volunteers Part B Alzheimer Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/69 (14.49%)      3/81 (3.70%)      17/125 (13.60%)      23/147 (15.65%)    
General disorders         
Application site erythema  1  3/69 (4.35%)  3 1/81 (1.23%)  1 0/125 (0.00%)  0 0/147 (0.00%)  0
Injection site erythema  1  1/69 (1.45%)  1 0/81 (0.00%)  0 1/125 (0.80%)  1 6/147 (4.08%)  6
Injection site haematoma  1  0/69 (0.00%)  0 0/81 (0.00%)  0 2/125 (1.60%)  2 8/147 (5.44%)  8
Injection site irritation  1  0/69 (0.00%)  0 0/81 (0.00%)  0 4/125 (3.20%)  4 1/147 (0.68%)  1
Injection site pain  1  0/69 (0.00%)  0 0/81 (0.00%)  0 2/125 (1.60%)  2 3/147 (2.04%)  3
Nervous system disorders         
Headache  1  4/69 (5.80%)  4 0/81 (0.00%)  0 2/125 (1.60%)  2 2/147 (1.36%)  2
Skin and subcutaneous tissue disorders         
Erythema  1  2/69 (2.90%)  2 1/81 (1.23%)  1 0/125 (0.00%)  0 0/147 (0.00%)  0
Vascular disorders         
Haematoma  1  1/69 (1.45%)  1 1/81 (1.23%)  1 7/125 (5.60%)  8 4/147 (2.72%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (13.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Juergen Hirschfeld
Organization: Piramal Imaging
Phone: 49 30 461 1246 15
Responsible Party: Life Molecular Imaging SA
ClinicalTrials.gov Identifier: NCT00750282     History of Changes
Other Study ID Numbers: 311741
2007-002256-42 ( EudraCT Number )
311741 ( Other Identifier: company internal )
First Submitted: September 9, 2008
First Posted: September 10, 2008
Results First Submitted: June 16, 2014
Results First Posted: July 16, 2014
Last Update Posted: July 24, 2014