Alzheimer Disease
Conditions
Brief summary
This study will evaluate whether visual interpretation of flortaucipir-PET (positron emission tomography) scans, examining patterns of tracer uptake at baseline, can predict the rate of clinically-meaningful cognitive decline due to AD after 18 months. All scans are acquired from cohorts of a previously completed study, I8D-MC-AZES (NCT02245737, lanabecestat, Eli Lilly and Company sponsor).
Interventions
DRUGflortaucipir F18
No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) at baseline will be read by independent, blinded readers. IV injection, 240 megabecquerel (MBq) (6.5 mCi), single dose in AZES
PROCEDUREBrain PET Scan
positron emission tomography (PET) scan of the brain
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Masking description
PET scans were obtained in an open-label fashion.
Intervention model description
Physician PET scan readers are participants, blinded to demographic and clinical data from the source PET scans.
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Scan Reader Criteria (5 total readers): * Board-certified in radiology or nuclear medicine * Professional experience interpreting PET scans Scan Criteria (205 total scans): * Former enrollment in AZES Study * Flortaucipir scan at baseline * clinical dementia rating - sum of boxes (CDR-SB) assessment at 18 months Scan Study Population (AZES Study): * 55 to 85 years * MCI due to AD or probable AD by National Institute on Aging-Alzheimer's Association criteria (Albert 2011 * mini-mental status exam (MMSE) of 20 to 30 inclusive * CDR global score of 0.5 (MCI), or 0.5 or 1 (AD) with a memory box score ≥ 0.5, and a score of ≤85 on the Delayed Memory Index of the Repeatable Battery for the Assessment of Neuropsychological Status. * Amyloid positive status confirmed by florbetapir PET or lumbar puncture
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Risk Ratio for AD Symptom Progression on CDR-SB | Within 18 months of scan | Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the primary endpoint as a worsening of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score of one point or more. The clinical dementia rating (CDR) examines 6 categories of cognitive functioning domains. Each domain is scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB was generated as the sum of the values in each of the 6 domains. The CDR-SB sum scores range from 0 to 18, with higher scores indicating greater cognitive impairment and a 1 point worsening is considered a clinically significant symptom change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Risk Ratio for AD Symptom Progression on Various Clinical Measures | Within 18 months of scan | Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the cognitive endpoints as follows: mini-mental status exam (MMSE) worsening of 3 points or greater, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) worsening of 4 points or greater, Pfeffer's Functional Activities Questionnaire (FAQ) worsening of 3 points or greater, CDR global worsening of greater than 0 points. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function. CDR global is scored on a 5 point scale (0, 0.5, 1, 2, 3) with higher scores indicating worsening cognitive function. |
| Mean Change in Cognitive/Functional Assessments | baseline and 18 months | Mean change in cognitive/functional measures baseline between τAD++ and non-τAD++ (determined by baseline tau status), calculated by Mixed Model Repeat Measures (MMRM). CDR-SB scores range from 0 to 18, with higher scores indicating worsening cognitive impairment. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function. |
| Inter-Reader Reliability of Reader Interpretation of Flortaucipir F 18 PET Imaging | baseline scan | As measured by Fleiss' Kappa across all scans read. Fleiss' kappa is a statistical measure for assessing the reliability of agreement between a fixed number of raters when assigning categorical ratings to a number of items or classifying items. Fleiss' kappa can range from -1 to 1 with 1 indicating perfect agreement between the readers. Read results binarized as τAD++ or non-τAD++. |
Countries
United States
Participant flow
Recruitment details
Scans were acquired from subjects previously enrolled in the AZES (NCT02245737) PET substudy (N=205), including mild AD (n=141) and mild cognitive impairment (MCI) due to AD (n=64).
Pre-assignment details
To be included in the study, subjects had to have a valid baseline flortaucipir PET scan and clinical dementia rating (CDR) assessments at baseline and 18 months.
Participants by arm
| Arm | Count |
|---|---|
| All Scans Mild AD and MCI due to AD from the flortaucipir PET scan arm | 205 |
| Total | 205 |
Baseline characteristics
| Characteristic | All Scans |
|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 7.74 |
| Flortaucipir PET Scan Result tAD- | 28 Participants |
| Flortaucipir PET Scan Result tAD+ | 15 Participants |
| Flortaucipir PET Scan Result tAD++ | 162 Participants |
| Mean CDR-SB | 3.69 units on a scale STANDARD_DEVIATION 1.475 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 27 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 172 Participants |
| Sex: Female, Male Female | 100 Participants |
| Sex: Female, Male Male | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 0 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Risk Ratio for AD Symptom Progression on CDR-SB
Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the primary endpoint as a worsening of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score of one point or more. The clinical dementia rating (CDR) examines 6 categories of cognitive functioning domains. Each domain is scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB was generated as the sum of the values in each of the 6 domains. The CDR-SB sum scores range from 0 to 18, with higher scores indicating greater cognitive impairment and a 1 point worsening is considered a clinically significant symptom change.
Time frame: Within 18 months of scan
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on CDR-SB | tAD++ | 119 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on CDR-SB | tAD+ | 10 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on CDR-SB | tAD- | 14 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on CDR-SB | tAD++ | 43 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on CDR-SB | tAD+ | 5 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on CDR-SB | tAD- | 14 Participants |
Comparison: Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysisp-value: 0.031395% CI: [1.028, 1.785]log linear model
Secondary
Inter-Reader Reliability of Reader Interpretation of Flortaucipir F 18 PET Imaging
As measured by Fleiss' Kappa across all scans read. Fleiss' kappa is a statistical measure for assessing the reliability of agreement between a fixed number of raters when assigning categorical ratings to a number of items or classifying items. Fleiss' kappa can range from -1 to 1 with 1 indicating perfect agreement between the readers. Read results binarized as τAD++ or non-τAD++.
Time frame: baseline scan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CMD (CDR-SB Change >=1) | Inter-Reader Reliability of Reader Interpretation of Flortaucipir F 18 PET Imaging | 0.754 kappa coefficient |
Secondary
Mean Change in Cognitive/Functional Assessments
Mean change in cognitive/functional measures baseline between τAD++ and non-τAD++ (determined by baseline tau status), calculated by Mixed Model Repeat Measures (MMRM). CDR-SB scores range from 0 to 18, with higher scores indicating worsening cognitive impairment. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function.
Time frame: baseline and 18 months
Population: All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| CMD (CDR-SB Change >=1) | Mean Change in Cognitive/Functional Assessments | CDR-SB | 2.22 units on a scale | Standard Error 0.215 |
| CMD (CDR-SB Change >=1) | Mean Change in Cognitive/Functional Assessments | MMSE | -4.89 units on a scale | Standard Error 0.377 |
| CMD (CDR-SB Change >=1) | Mean Change in Cognitive/Functional Assessments | ADAS-Cog11 | 6.53 units on a scale | Standard Error 0.66 |
| CMD (CDR-SB Change >=1) | Mean Change in Cognitive/Functional Assessments | FAQ | 5.22 units on a scale | Standard Error 0.537 |
| No CMD | Mean Change in Cognitive/Functional Assessments | FAQ | 2.68 units on a scale | Standard Error 0.895 |
| No CMD | Mean Change in Cognitive/Functional Assessments | CDR-SB | 1.31 units on a scale | Standard Error 0.379 |
| No CMD | Mean Change in Cognitive/Functional Assessments | ADAS-Cog11 | 1.97 units on a scale | Standard Error 1.181 |
| No CMD | Mean Change in Cognitive/Functional Assessments | MMSE | -2.12 units on a scale | Standard Error 0.647 |
Comparison: MMRM testing the difference between CDR-SB least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.p-value: 0.0305Mixed Models Analysis
Comparison: MMRM testing the difference between MMSE least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.p-value: <0.0001Mixed Models Analysis
Comparison: MMRM testing the difference between ADAS-Cog11 least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.p-value: 0.0006Mixed Models Analysis
Comparison: MMRM testing the difference between FAQ least squares mean changes of tAD++ and Non-tAD++ (tAD+ and tAD-). The unstructured covariance structure (UN) was used.p-value: 0.0097Mixed Models Analysis
Secondary
Risk Ratio for AD Symptom Progression on Various Clinical Measures
Baseline flortaucipir F 18 PET imaging results were determined by majority read (see Baseline Characteristics for description). Clinically meaningful deterioration (CMD) was defined for the cognitive endpoints as follows: mini-mental status exam (MMSE) worsening of 3 points or greater, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) worsening of 4 points or greater, Pfeffer's Functional Activities Questionnaire (FAQ) worsening of 3 points or greater, CDR global worsening of greater than 0 points. MMSE scores range from 0 to 30 with lower scores indicating worsening cognitive function. ADAS-Cog11 scores range from 0 to 70 with higher scores indicating worsening cognitive function. FAQ scores range from 0 to 30 with higher scores indicating worsening cognitive function. CDR global is scored on a 5 point scale (0, 0.5, 1, 2, 3) with higher scores indicating worsening cognitive function.
Time frame: Within 18 months of scan
Population: All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD- | 15 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD++ | 112 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD+ | 6 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD++ | 98 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD+ | 6 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD- | 8 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD++ | 111 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD+ | 9 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD- | 14 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD++ | 71 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD+ | 7 Participants |
| CMD (CDR-SB Change >=1) | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD- | 9 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD+ | 8 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD++ | 47 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD++ | 49 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD++ | 91 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD+ | 8 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | MMSE | tAD- | 13 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD+ | 5 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD++ | 59 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | CDR Global | tAD- | 19 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD+ | 8 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | FAQ | tAD- | 14 Participants |
| No CMD | Risk Ratio for AD Symptom Progression on Various Clinical Measures | ADAS-Cog | tAD- | 20 Participants |
Comparison: Risk ratio for MMSE CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysisp-value: 0.083395% CI: [0.962, 1.886]log linear model
Comparison: Risk ratio for ADAS-Cog11 CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysisp-value: 0.014195% CI: [1.122, 2.796]log linear model
Comparison: Risk ratio for FAQ CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysisp-value: 0.063995% CI: [0.984, 1.776]log linear model
Comparison: Risk ratio for CDR Global CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysisp-value: 0.281495% CI: [0.815, 2.02]log linear model