Alzheimer's Disease
Conditions
Brief summary
A Phase 2/3 cross-sectional and longitudinal observational study evaluating imaging characteristics of flortaucipir in control subjects and patients with clinically defined MCI and AD dementia (AD).
Detailed description
This study was conducted in 2 phases: a Phase 2 Exploratory Phase and a Phase 3 Confirmatory Phase. An overarching goal of the Exploratory Phase of this protocol was to further investigate the pattern of flortaucipir PET imaging across the disease course, in cognitively healthy subjects through patients with cognitive decline. To accomplish this goal, the protocol investigated flortaucipir results in younger and older cognitively healthy normal volunteers and patients with clinical diagnoses for cognitive complaints, ranging from MCI to mild and moderate AD dementia. Additionally, the Exploratory Phase of this protocol investigated relationships between flortaucipir PET signal and cognitive decline over the 18-month study period. The second, Confirmatory Phase of the study was designed to provide independent validation of the relationships observed in the exploratory analyses of the first phase. In particular, the goal of the second phase was to confirm the relationship between flortaucipir uptake in the brain as measured by PET signals at baseline and the subsequent rate of cognitive decline observed over the 18-month longitudinal follow up.
Interventions
DRUGflorbetapir F 18
DRUGFlortaucipir F18
PROCEDUREBrain PET Scan
positron emission tomography (PET) scan of the brain
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Outcomes Assessor)
Masking description
Applies only to confirmatory phase: the independent readers are blinded to all clinical information.
Intervention model description
All subjects in both the exploratory and confirmatory phases of the study, receive both florbetapir and florbetapir scans, regardless of subgroup assignment.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Exploratory Cognitively Healthy Subjects * ≥ 20 to ≤ 40 years of age OR ≥ 50 years of age * Mini-mental state examination (MMSE) ≥ 29 * No significant history of cognitive impairment Exploratory MCI Subjects * ≥ 50 years of age * MMSE ≥ 24 * Have MCI consistent with National Institute on Aging-Alzheimer's Association (NIA-AA) working group's diagnostic guidelines for AD * Have a study partner that can report on subject's activities of daily living Exploratory AD Subjects * ≥ 50 years of age * MMSE \> 10 * Have possible or probable AD based on the NIA-AA working group's diagnostic guidelines for AD * Have a study partner that can report on subject's activities of daily living Confirmatory Subjects * ≥ 50 years of age * MMSE ≥ 20 and ≤ 27 * Cognitively impaired subjects with either MCI or dementia with a suspected neurodegenerative cause * Have a study partner that can report on subject's activities of daily living
Exclusion criteria
* Current clinically significant psychiatric disease * Evidence of structural brain abnormalities * History of moderate or severe traumatic brain injury * Current clinically significant cardiovascular disease or ECG abnormalities, or additional risk factors for Torsades de Pointes * Current clinically significant infectious disease, endocrine or metabolic disease, pulmonary, renal or hepatic impairment, or cancer * History of alcohol or substance abuse or dependence * Females of childbearing potential who are not surgically sterile, not refraining from sexual activity or not using reliable methods of contraception * Have received or participated in a trial with investigational medications in the past 30 days * Have had a non-study related radiopharmaceutical imaging or treatment procedure within 7 days prior to the study imaging session.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | between baseline and 18 months | Confirm the relationship between neocortical flortaucipir uptake and the subsequent rate of cognitive decline at longitudinal follow up that was observed in the Exploratory Phase of the study. Patients were assigned to groups by majority classification of the flortaucipir positron emission tomography (PET) scan by five independent imaging physicians. Clinically meaningful cognitive and functional deterioration was defined as a 1 point or greater worsening on clinical dementia rating - sum of boxes (CDR-SB) score over the follow-up period. |
| Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | baseline scan | Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain. |
| Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status | baseline and 18 months | Assess the rate of change of tau deposition as measured by flortaucipir uptake (SUVr) over time. Change = 18 months SUVr - baseline SUVr. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | baseline and 18 months | This analysis used dichotomized CDR-SB change as a truth standard (1 point or more worsening = true positive vs. less than 1 point worsening = true negative) to assess the diagnostic performance of baseline Advanced AD tau status (τAD++) as determined by flortaucipir scan interpretation. Sensitivity and Specificity were calculated for each of the 5 independent imaging readers. Sensitivity is the percentage of true positive cases correctly identified by an Advanced AD pattern scan. Specificity is the percentage of true negative cases correctly identified by scans that were not classified as Advanced AD pattern. |
| Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | baseline scan | Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain. |
Countries
United States
Participant flow
Recruitment details
Exploratory cohort subjects were enrolled starting in Dec 2013. Confirmatory cohort subjects were enrolled Dec 2014-July 2017. Exploratory cohort subjects were not eligible for the confirmatory phase.
Pre-assignment details
To ensure a distribution of disease severity in the confirmatory phase, a target was set to recruit at least one-third of the enrolled subjects with dementia
Participants by arm
| Arm | Count |
|---|---|
| Exploratory Young Cognitively Healthy Subjects Male or female subjects ≥20 to ≤40 years of age with MMSE ≥29 | 16 |
| Exploratory Older Cognitively Healthy Subjects Male or female subjects ≥50 years of age with MMSE ≥29 | 58 |
| Exploratory MCI Subjects Subjects with mild cognitive impairment consistent with National Institute of Aging (NIA)-Alzheimer's Association working group's diagnostic guidelines for AD (Albert et al. 2011) and MMSE ≥24 | 98 |
| Exploratory AD Subjects Subjects with possible or probable AD dementia based on the NIA-Alzheimer's Association working group's diagnostic guidelines for AD (McKhann et al. 2011) and MMSE \>10 | 51 |
| Confirmatory Subjects MCI Clinically diagnosed mild cognitive impairment with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27 | 98 |
| Confirmatory Subjects AD Clinically diagnosed dementia with a suspected neurodegenerative cause with an MMSE score ≥20 and ≤27 | 62 |
| Total | 383 |
Baseline characteristics
| Characteristic | Exploratory Young Cognitively Healthy Subjects | Exploratory Older Cognitively Healthy Subjects | Exploratory MCI Subjects | Exploratory AD Subjects | Total | Confirmatory Subjects MCI | Confirmatory Subjects AD |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.9 years STANDARD_DEVIATION 4.88 | 68.5 years STANDARD_DEVIATION 10.29 | 70.8 years STANDARD_DEVIATION 9.3 | 73.9 years STANDARD_DEVIATION 9.01 | 72.9 years STANDARD_DEVIATION 9.61 | 72.5 years STANDARD_DEVIATION 9.69 | 73.6 years STANDARD_DEVIATION 9.53 |
| Clinical Dementia Rating - Sum of Boxes (CDR-SB) | — | — | — | — | 3.4 units on a scale STANDARD_DEVIATION 1.88 | 2.8 units on a scale STANDARD_DEVIATION 1.73 | 4.3 units on a scale STANDARD_DEVIATION 1.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 15 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 57 Participants | 94 Participants | 51 Participants | 368 Participants | 93 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 9 Participants | 7 Participants | 2 Participants | 24 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 47 Participants | 89 Participants | 47 Participants | 349 Participants | 94 Participants | 61 Participants |
| Sex: Female, Male Female | 7 Participants | 26 Participants | 49 Participants | 28 Participants | 184 Participants | 44 Participants | 30 Participants |
| Sex: Female, Male Male | 9 Participants | 32 Participants | 49 Participants | 23 Participants | 199 Participants | 54 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 58 | 0 / 98 | 0 / 51 | 0 / 98 | 0 / 62 |
| other Total, other adverse events | 3 / 16 | 17 / 58 | 21 / 98 | 13 / 51 | 13 / 98 | 0 / 62 |
| serious Total, serious adverse events | 0 / 16 | 0 / 58 | 1 / 98 | 0 / 51 | 0 / 98 | 0 / 62 |
Outcome results
Primary
Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline
Confirm the relationship between neocortical flortaucipir uptake and the subsequent rate of cognitive decline at longitudinal follow up that was observed in the Exploratory Phase of the study. Patients were assigned to groups by majority classification of the flortaucipir positron emission tomography (PET) scan by five independent imaging physicians. Clinically meaningful cognitive and functional deterioration was defined as a 1 point or greater worsening on clinical dementia rating - sum of boxes (CDR-SB) score over the follow-up period.
Time frame: between baseline and 18 months
Population: Subjects from the confirmatory phase with valid flortaucipir visual read and 9 or 18 month clinical follow-up.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Predicted to Progress | Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | Clinically meaningful progression | 36 Participants |
| Predicted to Progress | Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | Did Not Progress | 27 Participants |
| Not Predicted to Progress | Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | Clinically meaningful progression | 31 Participants |
| Not Predicted to Progress | Confirmatory Phase: Relationship Between Neocortical Flortaucipir Uptake and the Subsequent Rate of Cognitive Decline | Did Not Progress | 37 Participants |
Comparison: The specific hypothesis tested was that the hazard of progressing to the clinically meaningful event (defined as CDR-SB value change of at least 1 within 18 months) will be significantly greater for subjects with flortaucipir scans rated by majority interpretation as predicted to progress (Advanced AD scan pattern), as compared to subjects with scans rated as not predicted to progress (Moderate or Not AD scan pattern).p-value: 0.06795% CI: [0.968, 2.581]Cox proportional hazards
Primary
Exploratory Phase: Cross-sectional Flortaucipir Imaging Results
Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.
Time frame: baseline scan
Population: Analysis included all subjects who received an injection of flortaucipir, had valid quantifiable flortaucipir imaging data available, and valid quantifiable florbetapir PET data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Predicted to Progress | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ- SUVr | 1.03 standardized uptake value ratio (SUVr) | Standard Error 0.051 |
| Predicted to Progress | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ+ SUVr | 1.53 standardized uptake value ratio (SUVr) | Standard Error 0.037 |
| Not Predicted to Progress | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ- SUVr | 0.99 standardized uptake value ratio (SUVr) | Standard Error 0.029 |
| Not Predicted to Progress | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ+ SUVr | 1.26 standardized uptake value ratio (SUVr) | Standard Error 0.03 |
| Exploratory Older Cognitively Healthy Subjects | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ+ SUVr | 1.08 standardized uptake value ratio (SUVr) | Standard Error 0.093 |
| Exploratory Older Cognitively Healthy Subjects | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ- SUVr | 0.98 standardized uptake value ratio (SUVr) | Standard Error 0.029 |
| Exploratory Young Cognitively Healthy Subjects | Exploratory Phase: Cross-sectional Flortaucipir Imaging Results | Aβ- SUVr | 1.01 standardized uptake value ratio (SUVr) | Standard Error 0.039 |
Comparison: ANCOVA model comparing the mean SUVr between AD and Older Cognitively Healthy within amyloid positive group.p-value: <0.0001ANCOVA
Comparison: ANCOVA model comparing the mean SUVr between MCI and Older Cognitively Healthy within the amyloid positive group.p-value: 0.0622ANCOVA
Comparison: ANCOVA model comparing the mean SUVr between AD and MCI within the amyloid positive group.p-value: <0.0001ANCOVA
Primary
Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status
Assess the rate of change of tau deposition as measured by flortaucipir uptake (SUVr) over time. Change = 18 months SUVr - baseline SUVr.
Time frame: baseline and 18 months
Population: Analysis of flortaucipir SUVr Change Over Time by Amyloid Status, Exploratory Phase Efficacy Population (AD and MCI subjects only)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Predicted to Progress | Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status | 0.052359 standardized uptake value ratio (SUVr) | Standard Error 0.008536 |
| Not Predicted to Progress | Exploratory Phase: Longitudinal Change in Tau Deposition Over Time, by Amyloid Status | 0.000655 standardized uptake value ratio (SUVr) | Standard Error 0.002394 |
Comparison: SUVr change from baseline as dependent variable, baseline SUVr, age, and visit as independent variables, using an unstructured covariance structure for amyloid positive subjects only.p-value: <0.0001Mixed Models Analysis
Comparison: SUVr change from baseline as dependent variable, baseline SUVr, age, and visit as independent variables, using an unstructured covariance structure for amyloid negative subjects only.p-value: 0.7851Mixed Models Analysis
Secondary
Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read
This analysis used dichotomized CDR-SB change as a truth standard (1 point or more worsening = true positive vs. less than 1 point worsening = true negative) to assess the diagnostic performance of baseline Advanced AD tau status (τAD++) as determined by flortaucipir scan interpretation. Sensitivity and Specificity were calculated for each of the 5 independent imaging readers. Sensitivity is the percentage of true positive cases correctly identified by an Advanced AD pattern scan. Specificity is the percentage of true negative cases correctly identified by scans that were not classified as Advanced AD pattern.
Time frame: baseline and 18 months
Population: All confirmatory phase subjects who completed 18 months of follow-up for the cognitive endpoint were read by each reader
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 1 Sensitivity | 59.6 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 1 Specificity | 65.5 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 2 Sensitivity | 53.8 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 2 Specificity | 65.5 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 3 Sensitivity | 55.8 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 3 Specificity | 65.5 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 4 Sensitivity | 59.6 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 4 Specificity | 65.5 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 5 Sensitivity | 50.0 percentage of cases correctly identified |
| Predicted to Progress | Confirmatory Phase: Diagnostic Performance of Flortaucipir Visual Read | Reader 5 Specificity | 65.5 percentage of cases correctly identified |
Secondary
Exploratory Phase: Correlation Between Flortaucipir SUVr and Age
Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain.
Time frame: baseline scan
Population: Exploratory Young and Old healthy control subjects with a valid flortaucipir PET scan
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Predicted to Progress | Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 1.0083 standardized uptake value ratio (SUVr) | Standard Deviation 0.03905 |
| Not Predicted to Progress | Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 1.0203 standardized uptake value ratio (SUVr) | Standard Deviation 0.03693 |
| Exploratory Older Cognitively Healthy Subjects | Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 1.0110 standardized uptake value ratio (SUVr) | Standard Deviation 0.04149 |
| Exploratory Young Cognitively Healthy Subjects | Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 1.0010 standardized uptake value ratio (SUVr) | Standard Deviation 0.02604 |
| Exploratory Older Cognitively Healthy Subjects >=80 | Exploratory Phase: Correlation Between Flortaucipir SUVr and Age | 1.0048 standardized uptake value ratio (SUVr) | Standard Deviation 0.03978 |
Comparison: Pearson's correlation coefficientp-value: 0.4361Pearson