Alzheimer Disease, Mild Cognitive Impairment, Neurodegenerative Diseases
Conditions
Keywords
Amyloid imaging, Positron Emission Tomography, 18F-AV-45, florbetapir F 18, Diagnostic imaging
Brief summary
This study will investigate the performance of physician readers trained to read florbetapir-PET scans using electronic media training.
Detailed description
Avid has previously developed a florbetapir-PET scan binary read methodology and training program, which was successfully applied in studies 18F-AV-45-A08(NCT01565369), 18F-AV-45-A09(NCT01565382) and 18F-AV-45-A16(NCT01447719). In these previous studies, training was conducted in-person. Study 18F-AV-45-PT01 will evaluate an automated version of this training program suitable for web-based distribution. Nuclear medicine physicians will complete the automated training program then read the florbetapir-PET images from 151 subjects with repeat readings of 33 randomly selected images. Readers will rate each case as either positive for significant tracer accumulation in cortical gray matter or negative for significant tracer accumulation in cortical gray matter. The inter-rater reliability, sensitivity and specificity of the readers will be evaluated. The primary image set for determination of inter-reader agreement is comprised of images from 119 subjects from two previous clinical studies (A07\[NCT00857415\]/A16\[NCT01447719\] and A05\[NCT00702143\]). This included all 59 subjects who came to autopsy in Study A07(NCT00857415) and it's follow-up study, A16(NCT01447719), and a set of 60 cases randomly selected from Study A05(NCT00702143) subjects, including 20 cognitively-normal controls, 20 with mild cognitive impairment) MCI, 20 with AD. Subsequently, the protocol was amended to include all remaining A05(NCT00702143) MCI patients that were not used in the training program (n=32); 13 of these 32 scans presented for repeat reading (to increase the number of A05 MCI cases with repeated reads to 20). This increased the number of unique cases in the validation dataset to 151 scans with 33 scans repeated yielding a total of 184 scans reviewed by the readers.
Interventions
DRUGflorbetapir F 18
No study drug will be administered in this study - scans previously acquired in in Study A05(NCT00702143) and A07(NCT00857415) will be read
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Eligibility for subjects scans to be used in this study is determined by subject's eligibility/enrollment in Study A05 (NCT00702143) or A07 (NCT00857415). Alzheimer's disease (AD) group key eligibility criteria (from Study A05\[NCT00702143\]): * Male or female at least 50 years of age * Have probable AD per National Institute of Neurological and Communication Disorders and Stroke (NINCDS) criteria * Mini mental state exam (MMSE) score between 10 and 24 inclusive Mild cognitive impairment group key eligibility criteria (from Study A05\[NCT00702143): * Male or female at least 50 years of age * Complaints of memory or cognitive decline corroborated by an informant * Clinical dementia rating of 0.5 * No obvious cause for cognitive impairment (eg, head trauma or stroke) * Cognitive impairment onset within the past year * MMSE score greater than 24 Cognitively normal volunteer group key eligibility criteria (from Study A05\[NCT00702143\]): * Male or female at least 50 years of age * MMSE score greater than or equal to 29 and cognitively normal by informant report and psychometric test battery at screening Autopsy cohort key eligibility criteria (from Study A07\[NCT00857415\]): * Male or female 18 years or older * Projected life expectancy of less than 6 months * Consent to brain donation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inter-rater Reliability | Scan acquired 50-60 min post-injection | Measure of agreement among five readers using a binary read method (amyloid positive/negative) calculated using Fleiss' kappa. All scans were read in a blinded fashion without access to clinical information. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | at autopsy, within 2 years of scan | Calculated as the percent of true positives which are correctly identified |
| Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | at autopsy, within 2 years of scan | Calculated as the percent of true negatives which are correctly identified |
Other
| Measure | Time frame | Description |
|---|---|---|
| Median Sensitivity and Specificity vs. CERAD Diagnosis | Baseline scan | Median sensitivity and specificity for 5 independent readers to detect moderate to frequent amyloid plaques (per CERAD criteria). |
Participant flow
Recruitment details
NO SUBJECTS WERE ENROLLED IN THIS STUDY - this study re-read scans obtained in other clinical studies
Participants by arm
| Arm | Count |
|---|---|
| Florbetapir-PET Scans All subjects with a valid florbetapir-PET scan (59 from study A07/A16 and 92 from study A05) | 151 |
| Total | 151 |
Baseline characteristics
| Characteristic | Florbetapir-PET Scans |
|---|---|
| Age Continuous | 74.9 years STANDARD_DEVIATION 11.87 |
| Region of Enrollment United States | 151 participants |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Inter-rater Reliability
Measure of agreement among five readers using a binary read method (amyloid positive/negative) calculated using Fleiss' kappa. All scans were read in a blinded fashion without access to clinical information.
Time frame: Scan acquired 50-60 min post-injection
Population: 59 autopsy subjects (study A07\[NCT00857415\]/A16\[NCT01447719\]) + 20 healthy controls + 20 mild cognitive impairment + 20 AD (from study A05\[NCT00702143\])
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Inter-rater Reliability | 0.81 kappa statistic |
Secondary
Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease)
Calculated as the percent of true positives which are correctly identified
Time frame: at autopsy, within 2 years of scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 2 | 92 percentage of positive cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 4 | 87 percentage of positive cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 3 | 69 percentage of positive cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 5 | 82 percentage of positive cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 1 | 79 percentage of positive cases IDed |
| Autopsy Within One Year of Scan | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 5 | 89 percentage of positive cases IDed |
| Autopsy Within One Year of Scan | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 1 | 86 percentage of positive cases IDed |
| Autopsy Within One Year of Scan | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 2 | 100 percentage of positive cases IDed |
| Autopsy Within One Year of Scan | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 3 | 75 percentage of positive cases IDed |
| Autopsy Within One Year of Scan | Sensitivity of Florbetapir-PET to Detect Moderate to Frequent Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 4 | 93 percentage of positive cases IDed |
Secondary
Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease)
Calculated as the percent of true negatives which are correctly identified
Time frame: at autopsy, within 2 years of scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 2 | 90 percentage of negative cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 4 | 95 percentage of negative cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 3 | 95 percentage of negative cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 5 | 95 percentage of negative cases IDed |
| Florbetapir-PET Scans Primary Analysis Group | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 1 | 90 percentage of negative cases IDed |
| Autopsy Within One Year of Scan | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 5 | 100 percentage of negative cases IDed |
| Autopsy Within One Year of Scan | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 1 | 89 percentage of negative cases IDed |
| Autopsy Within One Year of Scan | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 2 | 89 percentage of negative cases IDed |
| Autopsy Within One Year of Scan | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 3 | 94 percentage of negative cases IDed |
| Autopsy Within One Year of Scan | Specificity of Florbetapir-PET to Detect no or Sparse Beta-amyloid Neuritic Plaques (Probable/Definite Alzheimer's Disease) | Reader 4 | 94 percentage of negative cases IDed |
Post Hoc
Individual Reader Results (All Scans With Autopsy)
Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 39 positive and 20 negative scans based on histopathology at autopsy.
Time frame: Baseline scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 1 - False Negatives | 8 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 1 - False Positives | 2 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 2 - False Negatives | 3 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 2 - False Positives | 2 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 3 - False Negatives | 12 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 3 - False Positives | 1 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 4 - False Negatives | 5 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 4 - False Positives | 1 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 5 - False Negatives | 7 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (All Scans With Autopsy) | Reader 5 - False Positives | 1 florbetapir scans |
Post Hoc
Individual Reader Results (Autopsy Within 1 Year of Scan)
Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 28 positive and 18 negative scans based on histopathology at autopsy.
Time frame: Baseline scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 1 - False Negatives | 4 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 1 - False Positives | 2 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 2 - False Negatives | 0 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 2 - False Positives | 2 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 3 - False Negatives | 7 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 3 - False Positives | 1 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 4 - False Negatives | 2 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 4 - False Positives | 1 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 5 - False Negatives | 3 florbetapir scans |
| Florbetapir-PET Scans Primary Analysis Group | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 5 - False Positives | 0 florbetapir scans |
Post Hoc
Inter-reader Reliability
Measure of agreement among multiple readers using binary read method (Fleiss' kappa). Where available, histopathology analysis at autopsy was the truth standard (TS).
Time frame: Scan acquired 50-60 min post-injection
Population: 59 from study A07(NCT00857415)/A16(NCT01447719) and 92 from study A05(NCT00702143)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | All subjects [n=151] | 0.83 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | All subjects with a TS [n=59] | 0.75 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | All subjects without a TS [n=92] | 0.88 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | AD [n=49] (29 with TS; 20 no TS) | 0.67 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | MCI [n=57] (5 with TS; 52 no TS) | 0.91 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | Cognitively normal without TS [n=20] | 0.83 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | Cognitively normal with TS [n=12] | 0.73 kappa statistic |
| Florbetapir-PET Scans Primary Analysis Group | Inter-reader Reliability | Other (non-AD) dementia with TS [n=13] | 0.52 kappa statistic |
Other Pre-specified
Median Sensitivity and Specificity vs. CERAD Diagnosis
Median sensitivity and specificity for 5 independent readers to detect moderate to frequent amyloid plaques (per CERAD criteria).
Time frame: Baseline scan
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Florbetapir-PET Scans Primary Analysis Group | Median Sensitivity and Specificity vs. CERAD Diagnosis | Sensitivity | 82 percentage of true positives/negatives |
| Florbetapir-PET Scans Primary Analysis Group | Median Sensitivity and Specificity vs. CERAD Diagnosis | Specificity | 95 percentage of true positives/negatives |