Alzheimer's Disease
Conditions
Brief summary
This study is designed to determine the effectiveness of florbetapir (18F) in changing patient management and to evaluate the association between scan status and cognitive decline.
Interventions
Single i.v. bolus injection of 370MBq (10 mCi) followed by saline flush, 50 minutes prior to imaging, 10 minute image duration
Sponsors
Eli Lilly and Company
Avid Radiopharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Patients may be enrolled in the mild impairment (not demented) group if the following criteria are met: 1. Males or females ≥ 50 to \<= 90 years of age. 2. Have cognitive decline verified by a study partner or cognitive impairment verified by the study physician. 3. Have a study partner who provides separate consent and is willing to accompany the patient on all of the study visits. 4. Have an MMSE score of 24 to 30 inclusive. 5. Can tolerate a 10-minute PET scan. 6. Have the ability to cooperate and comply with all study procedures. 7. Have an enrolling physician who has less than high confidence in their diagnosis for the patient related to the cognitive decline at the time of enrollment. 8. Ability to provide informed consent for study procedures. Patients may be enrolled in the dementia group if the following criteria are met: 1. Are males or females ≥ 50 to \<= 90 years of age. 2. Meet clinical criteria for dementia. 3. Have a caregiver who provides separate consent and is willing to accompany the patient on all of the study visits. 4. Have an MMSE score of 16 to 24 inclusive. 5. Have not received a clinical examination and/or laboratory test results that strongly indicates a non-neurodegenerative cause for the patients cognitive impairment. 6. Can tolerate a 10-minute PET scan. 7. Have the ability to cooperate and comply with all study procedures. 8. Have an enrolling physician who has less than high confidence in their diagnosis for the patient related to the cognitive decline at the time of enrollment. 9. Ability to provide informed consent for study procedures. (If the patient is incapable of giving informed consent, the patient's legal representative may consent on behalf of the patient but the patient must still confirm assent. This person may serve as the study partner as well).
Exclusion criteria
Patients will be excluded from enrollment if they: 1. Have a current serious or unstable illness; 2. The patient or enrolling physician knows the result of a previous amyloid imaging scan; 3. The patient has a known brain lesion, pathology or alternative diagnosis that strongly explains the patient's clinical presentation; 4. Are receiving any investigational medications, or have participated in a trial with investigational medications within the last 30 days; 5. Have ever participated in an experimental study with an amyloid targeting agent (e.g. anti-amyloid immunotherapy, γ -secretase or β -secretase inhibitor) unless it can be documented that the patient received only placebo during the course of the trial; 6. Have had a radiopharmaceutical imaging or treatment procedure within 7 days prior to the study imaging session; or 7. Are females of childbearing potential who are not surgically sterile, not refraining from sexual activity or not using reliable methods of contraception. Patients will also be excluded from enrollment if their enrolling physician: 1. Does not consider Alzheimer's disease as a potential cause of the patient's cognitive decline. 2. Is not the primary physician taking care of the patient with respect to the management of their cognitive impairment. 3. Cannot categorize the patient as either: a) having a documented and completed evaluation for cognitive decline within the past 18 months old; or b) currently undergoing evaluation for cognitive decline. 4. Is unwilling to suspend all testing and other evaluation procedures between the time of the baseline evaluation of the enrolling physician's diagnosis and management plan and the time the completion of the PET scan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and Diagnostic Change in Patient Management | Baseline and 3 months | Comparison of the percentage of patients who have a change in management from baseline to 3 months for patients who receive scan results immediately (intervention arm) and those who receive scan results 12 months later (control arm). |
| Change in ADAS-Cog 11 Total Score | Baseline and 12 months | Change from baseline in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) 11 Score in patients with mild impairment by positive or negative florbetapir (18F) PET scan result (Aß+/Aß-). ADAS-Cog scores (range 0-70) indicate performance on a series of 11 cognitive tasks where 0 indicates the highest level of cognitive performance and 70 indicates the lowest level of cognitive performance. Change in ADAS-Cog scores were calculated by subtracting the baseline score from the 12 month score. A change in ADAS-Cog greater than 0 indicates a deterioration in cognitive performance whereas a change in ADAS-Cog less than 0 indicates improved cognitive performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Patient Management: Advice/Counseling | Baseline and 3 months | Comparison of the percentage of patients in the intervention and control arms who have a change in management relating to advice and counseling from baseline to 3 months. |
| Change in Patient's Clinical Diagnosis | Baseline and 3 months | Comparison of the percentage of patients who have a change in diagnosis from baseline to 3 months for patients in the intervention and control arms for whom the scan result was not predicted by the initial diagnosis. |
| Change in Patient Management: Individual Categories | Baseline and 3 months | Compare the percentage of patients with a change from baseline in the individual patient management categories at 3 months in the interventional and control arms.The individual categories are: Major diagnostic tests, Alzheimer's/cognition medication, neuropsychological tests, physician follow-up for re-evaluation or specialist referral. |
| Change in Caregiver Self-efficacy | Baseline and 3 months | Comparison of the change in self-efficacy between intervention and control arms. Change in self-efficacy is defined as the difference between total score on the Fortinsky: Family caregivers' self-efficacy for managing dementia scale at Follow-up (3 months) and baseline. Self-efficacy for managing dementia is defined in terms of specific behaviors or tasks that can be learned, and that are highly relevant to daily management of the disease process. The scale consists of 10 questions, each with responses ranging from 1 (not at all certain) to 10 (very certain). The total score is calculated by summing the response for each item. The total score ranges from 10 to 100, with increasing scores representing increasing caregiver self-efficacy. |
| Change in Diagnostic Confidence | Baseline and 3 months | Comparison of the percentage point change in the physician's diagnostic confidence from baseline to month 3 in the intervention and control arms for patients whose scan result was predicted by their baseline clinical diagnosis. Diagnostic confidence was recorded by the physician as a whole number percent from 0-100% and the change in confidence was calculated by subtracting the baseline confidence from the confidence recorded at the specified timepoint. Values greater than zero reflect increased diagnostic confidence; values less than zero reflect decreased diagnostic confidence. |
Countries
France, Italy, United States
Participant flow
Pre-assignment details
641 patients enrolled in the study. 21 patients withdrew before receiving a florbetapir (F18) PET scan. 620 patients received florbetapir and comprise the Safety Population; 2 patients did not have a valid PET scan. Therefore; 618 patients were randomized to the intervention or control arms and comprise the Efficacy Population.
Participants by arm
| Arm | Count |
|---|---|
| Intervention Subjects will receive florbetapir (18F) PET scans and physicians will have immediate access to PET scan results.
florbetapir (18F): Single i.v. bolus injection of 370MBq (10 mCi) followed by saline flush, 50 minutes prior to imaging, 10 minute image duration | 308 |
| Control Subjects will receive florbetapir (18F) PET scans but physicians will be blinded to PET scan results for 12 months
florbetapir (18F): Single i.v. bolus injection of 370MBq (10 mCi) followed by saline flush, 50 minutes prior to imaging, 10 minute image duration | 310 |
| Total | 618 |
Baseline characteristics
| Characteristic | Intervention | Control | Total |
|---|---|---|---|
| Age, Continuous | 73.1 years STANDARD_DEVIATION 8.2 | 72.7 years STANDARD_DEVIATION 7.94 | 72.9 years STANDARD_DEVIATION 8.07 |
| Region of Enrollment France | 87 participants | 87 participants | 174 participants |
| Region of Enrollment Italy | 109 participants | 112 participants | 221 participants |
| Region of Enrollment United States | 112 participants | 111 participants | 223 participants |
| Sex: Female, Male Female | 142 Participants | 160 Participants | 302 Participants |
| Sex: Female, Male Male | 166 Participants | 150 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 620 |
| serious Total, serious adverse events | 2 / 620 |
Outcome results
Primary
Change in ADAS-Cog 11 Total Score
Change from baseline in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) 11 Score in patients with mild impairment by positive or negative florbetapir (18F) PET scan result (Aß+/Aß-). ADAS-Cog scores (range 0-70) indicate performance on a series of 11 cognitive tasks where 0 indicates the highest level of cognitive performance and 70 indicates the lowest level of cognitive performance. Change in ADAS-Cog scores were calculated by subtracting the baseline score from the 12 month score. A change in ADAS-Cog greater than 0 indicates a deterioration in cognitive performance whereas a change in ADAS-Cog less than 0 indicates improved cognitive performance.
Time frame: Baseline and 12 months
Population: Analysis population for this endpoint only includes those patients with mild cognitive impairment, and who reported both a baseline and follow-up value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Change in ADAS-Cog 11 Total Score | 0.95 units on a scale | Standard Error 0.38 |
| Control | Change in ADAS-Cog 11 Total Score | 1.29 units on a scale | Standard Error 0.43 |
p-value: 0.56895% CI: [-1.54, 0.84]ANCOVA
Primary
Clinical and Diagnostic Change in Patient Management
Comparison of the percentage of patients who have a change in management from baseline to 3 months for patients who receive scan results immediately (intervention arm) and those who receive scan results 12 months later (control arm).
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients with both a baseline and follow-up value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Clinical and Diagnostic Change in Patient Management | 68.0 percentage of patients |
| Control | Clinical and Diagnostic Change in Patient Management | 55.5 percentage of patients |
p-value: 0.00295% CI: [1.22, 2.38]Chi-squared
Secondary
Change in Caregiver Self-efficacy
Comparison of the change in self-efficacy between intervention and control arms. Change in self-efficacy is defined as the difference between total score on the Fortinsky: Family caregivers' self-efficacy for managing dementia scale at Follow-up (3 months) and baseline. Self-efficacy for managing dementia is defined in terms of specific behaviors or tasks that can be learned, and that are highly relevant to daily management of the disease process. The scale consists of 10 questions, each with responses ranging from 1 (not at all certain) to 10 (very certain). The total score is calculated by summing the response for each item. The total score ranges from 10 to 100, with increasing scores representing increasing caregiver self-efficacy.
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients with both a baseline and follow-up value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Change in Caregiver Self-efficacy | 0.16 units on a scale | Standard Error 1.24 |
| Control | Change in Caregiver Self-efficacy | 0.00 units on a scale | Standard Error 1.26 |
p-value: 0.92595% CI: [-3.2, 3.53]ANCOVA
Secondary
Change in Diagnostic Confidence
Comparison of the percentage point change in the physician's diagnostic confidence from baseline to month 3 in the intervention and control arms for patients whose scan result was predicted by their baseline clinical diagnosis. Diagnostic confidence was recorded by the physician as a whole number percent from 0-100% and the change in confidence was calculated by subtracting the baseline confidence from the confidence recorded at the specified timepoint. Values greater than zero reflect increased diagnostic confidence; values less than zero reflect decreased diagnostic confidence.
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients whose scan result was predicted by their baseline clinical diagnosis and recorded both a baseline and follow-up value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Change in Diagnostic Confidence | 23.54 Percentage Point | Standard Error 1.13 |
| Control | Change in Diagnostic Confidence | 2.85 Percentage Point | Standard Error 1.15 |
Comparison: Comparison of change in diagnostic confidence at follow-up (3 months)p-value: <0.00195% CI: [18.95, 22.43]ANCOVA
Secondary
Change in Patient Management: Advice/Counseling
Comparison of the percentage of patients in the intervention and control arms who have a change in management relating to advice and counseling from baseline to 3 months.
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients with both a baseline and follow-up value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Change in Patient Management: Advice/Counseling | 64.7 percentage of patients |
| Control | Change in Patient Management: Advice/Counseling | 58.9 percentage of patients |
p-value: 0.14495% CI: [0.92, 1.78]Chi-squared
Secondary
Change in Patient Management: Individual Categories
Compare the percentage of patients with a change from baseline in the individual patient management categories at 3 months in the interventional and control arms.The individual categories are: Major diagnostic tests, Alzheimer's/cognition medication, neuropsychological tests, physician follow-up for re-evaluation or specialist referral.
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients with both a baseline and follow-up value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intervention | Change in Patient Management: Individual Categories | Alzheimer's/Cognitive Medication | 35.7 percentage of patients |
| Intervention | Change in Patient Management: Individual Categories | Physician Follow-up for Re-evaluation | 15.0 percentage of patients |
| Intervention | Change in Patient Management: Individual Categories | Neuropsychological Tests | 14.7 percentage of patients |
| Intervention | Change in Patient Management: Individual Categories | Specialist Referral | 30.7 percentage of patients |
| Intervention | Change in Patient Management: Individual Categories | Major Diagnostic Tests | 21 percentage of patients |
| Control | Change in Patient Management: Individual Categories | Specialist Referral | 23.4 percentage of patients |
| Control | Change in Patient Management: Individual Categories | Major Diagnostic Tests | 20.4 percentage of patients |
| Control | Change in Patient Management: Individual Categories | Alzheimer's/Cognitive Medication | 22.1 percentage of patients |
| Control | Change in Patient Management: Individual Categories | Neuropsychological Tests | 9.7 percentage of patients |
| Control | Change in Patient Management: Individual Categories | Physician Follow-up for Re-evaluation | 14.0 percentage of patients |
Comparison: Major Diagnostic Testsp-value: 0.85795% CI: [0.7, 1.54]Chi-squared
Comparison: Alzheimer's/Cognitive Medicationp-value: <0.00195% CI: [1.36, 2.81]Chi-squared
Comparison: Neuropsychological Testsp-value: 0.06395% CI: [0.97, 2.64]Chi-squared
Comparison: Physician Follow-up for Re-evaluationp-value: 0.74195% CI: [0.69, 1.7]Chi-squared
Comparison: Specialist Referralp-value: 0.04695% CI: [1.01, 2.08]Chi-squared
Secondary
Change in Patient's Clinical Diagnosis
Comparison of the percentage of patients who have a change in diagnosis from baseline to 3 months for patients in the intervention and control arms for whom the scan result was not predicted by the initial diagnosis.
Time frame: Baseline and 3 months
Population: Analysis population for this endpoint only includes those patients whose scan result was not predicted by their baseline clinical diagnosis and recorded both a baseline and follow-up value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Change in Patient's Clinical Diagnosis | 85.6 percentage of patients |
| Control | Change in Patient's Clinical Diagnosis | 11.9 percentage of patients |
p-value: <0.00195% CI: [20, 96.12]Chi-squared