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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Flortaucipir PET Scan | Experimental | No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) will be read by independent, blinded readers. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| flortaucipir F18 | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Within 18 months of scan |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Scan Reader Criteria (5 total readers):
Scan Criteria (205 total scans):
Scan Study Population (AZES Study):
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Avid Radiopharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| American College of Radiology | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33587110 | Derived | Lu M, Pontecorvo MJ, Devous MD Sr, Arora AK, Galante N, McGeehan A, Devadanam C, Salloway SP, Doraiswamy PM, Curtis C, Truocchio SP, Flitter M, Locascio T, Devine M, Zimmer JA, Fleisher AS, Mintun MA; AVID Collaborators. Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials. JAMA Neurol. 2021 Apr 1;78(4):445-453. doi: 10.1001/jamaneurol.2020.5505. |
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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.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | All Subjects | Mild AD and MCI due to AD from the flortaucipir PET scan arm |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Scans | Mild AD and MCI due to AD from the flortaucipir PET scan arm |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Count of Participants | Participants | Within 18 months of scan |
|
Not applicable, as no new patients received treatment as part of this study.
Adverse event data were not collected in this study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Single Arm, Randomly Sequenced Flortaucipir F18 Scans | No study drug was administered for this study. Scans were previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) and were read by five independent, blinded readers. Flortaucipir F18: No study drug was administered for this study. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Avid Radiopharmaceuticals, Inc. | 215-298-0700 | clinicaloperations@avidrp.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 12, 2019 | Jun 27, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 16, 2019 | Jun 27, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C000591008 | 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole |
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Physician PET scan readers are participants, blinded to demographic and clinical data from the source PET scans.
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PET scans were obtained in an open-label fashion.
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| Brain PET Scan | Procedure | positron emission tomography (PET) scan of the brain |
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| Within 18 months of scan |
| 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. | baseline and 18 months |
| 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++. | baseline scan |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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| Flortaucipir PET Scan Result | Majority read result of 5 independent readers. τAD++ (a pattern indicating spread of aggregated tau beyond the posterolateral temporal [PLT] lobe or occipital lobe); τAD+ (a pattern indicating aggregated tau confined to PLT and/or occipital lobe); or τAD- (inconsistent with an AD pattern). | Count of Participants | Participants |
|
| Mean CDR-SB | Mean Clinical Dementia Rating - Sum of Boxes Score (CDR-SB). The CDR scale (Berg 1988) examines 6 cognitive functioning domains individually on a scale of 0 to 3. CDR Sum of Boxes is generated by summing the total score across domains. Scores range from 0 to 18, with higher scores indicating higher levels of cognitive impairment. | Mean | Standard Deviation | units on a scale |
|
| OG001 | No CMD | Subjects who experienced less than a 1 point worsening in CDR-SB score over 18 months |
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| 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. | All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months. | Posted | Count of Participants | Participants | Within 18 months of scan |
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| 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. | All subjects were eligible for this analysis; however, row totals reflect subjects for whom clinical measure data was available at baseline and 18 months. | Posted | Least Squares Mean | Standard Error | units on a scale | baseline and 18 months |
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| 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++. | Posted | Number | 95% Confidence Interval | kappa coefficient | baseline scan |
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| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| tAD+ |
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| tAD- |
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| ADAS-Cog |
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| FAQ |
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| CDR Global |
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| Risk ratio for ADAS-Cog11 CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis | log linear model | Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score. | .0141 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Risk Ratio (RR) | 1.77 | 2-Sided | 95 | 1.122 | 2.796 | τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator | Other |
| Risk ratio for FAQ CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis | log linear model | Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score. | .0639 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Risk Ratio (RR) | 1.32 | 2-Sided | 95 | 0.984 | 1.776 | τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator | Other |
| Risk ratio for CDR Global CMD. Scan results were grouped into τAD++ vs. non-τAD++ (τAD+ and τAD-) for the analysis | log linear model | Adjusted for treatment arm (lanabecestat 20 mg, 50 mg, or placebo), baseline age, years of education (categorical), and baseline score. | .2814 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Risk Ratio (RR) | 1.28 | 2-Sided | 95 | 0.815 | 2.020 | τAD++ scans represent the numerator for risk, and τAD+/τAD- scans represent the denominator | Other |
| MMSE |
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| ADAS-Cog11 |
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| FAQ |
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| 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. | Mixed Models Analysis | Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo). | <0.0001 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Other |
| 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. | Mixed Models Analysis | Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo). | 0.0006 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Other |
| 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. | Mixed Models Analysis | Adjusted for baseline clinical score, age, years of education (categorical), and treatment arm (lanabecestat - 20mg or 50mg - or placebo). | 0.0097 | A priori threshold was two-sided 0.05. No adjustment for multiple comparisons. | Other |