|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
Mild Cognitive Impairment
Subjective Cognitive Decline Plus
|Medical condition in easily understood language
|Alzheimer’s disease (AD) is a progressive disorder and it is the most common cause of cognitive impairment and dementia.
|Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To test the hypothesis that the proportion of subjects for whom the managing physician reaches an aetiologic diagnosis with very high confidence (≥90%) at 12 weeks after baseline is higher for subjects who underwent amyloid PET imaging shortly after baseline than for subjects who have not yet undergone amyloid PET imaging (ie, subjects scheduled to undergo amyloid PET imaging at 8 months [±8 weeks] after baseline).
|Secondary objectives of the trial
|1) To assess the impact of amyloid PET imaging on Diagnosis and confidence (Time to communicate to the patient an aetiologic diagnosis with very high confidence (≥90%); Changes in the managing physician’s aetiologic diagnosis and diagnostic confidence over time; and the managing physician’s estimate of the likelihood that the patient’s symptoms are due to AD.
2) To assess the impact of amyloid PET imaging on diagnostic and patient management, including: change or early adoption of programs and pharmacologic treatments aimed to delay the onset or progression of cognitive impairment; and Use of medical resources.
3) To assess the impact of amyloid PET imaging on:
• Patient-related outcomes (cognition, anxiety, depression, coping skills, and quality of life)
• Cost of diagnostic workup to the aetiologic diagnosis with very high confidence (≥90%)
• Number of patients who are discharged from the memory centre and the reason for discharge
4) Imaging results assessment
|Trial contains a sub-study
|Principal inclusion criteria
|• The patient can be male or female and of any race or ethnicity.
• The patient must be 60 to 85 years of age (for patients with SCD-Plus) or 50 to 85 years of age (for patients with MCI or with dementia where AD is in the differential diagnosis).
• The patient must have a complaint (reported by the patient or by a caregiver) of cognitive problems that are considered by the managing physician to be possibly due to AD.
o The patient must be entering a diagnostic assessment for the cognitive complaint.
o The patient’s managing physician at the memory clinic must feel that knowledge of the patient’s brain amyloid status may increase diagnostic confidence and alter diagnosis and management.
o In some centres, the patient may receive diagnostic workup before being screened for this study. These patients can be enrolled in the study; however, if they are assigned to the Early Amyloid PET Imaging arm, the results of that workup must not be made available to the managing physician before the managing physician reviews the results of the amyloid PET scan.
• The patient must satisfy the diagnostic criteria for one of the following:
o Dementia, where AD is in the differential diagnosis
• The patient has an MRI and/or CT scan that excludes an intracranial mass or other lesion(s) that could explain cognitive impairment.
• The patient can complete all clinical visits according to the protocol.
• The patient can tolerate a 20-minute amyloid PET scan.
• The patient (or a legally acceptable representative, for patients with dementia) provides informed consent for study participation and data source verification.
• If the patient has dementia, he or she has a study partner willing and able to accompany him or her to all visits for the duration of the protocol
|Principal exclusion criteria
|Subjects must be excluded from participating in this study if they meet any of the following criteria:
• The patient has another confirmed condition that can fully account for the cognitive impairment (neuroinflammatory, neuroinfective, or neurodegenerative disease; multiple sclerosis; genetic disorders; HIV; brain injuries; neurosurgery aftereffects; major depressive episode; schizoaffective disorder; delusional disorder; delirium)
• The patient came to observation of the memory clinic for reasons other than diagnosis (disability assessment for social aids, cognitive assessment for driving license, etc.)
• The patient had a previous beta-amyloid imaging scan and/or has had other diagnostic workup (fluorodeoxyglucose [FDG]-PET and/or cerebrospinal fluid [CSF] analysis) for a cognitive complaint prior to the screening. (In some centres, the patient may receive a diagnostic workup before the screening for this study. These patients can be enrolled in the study only if the investigator is blinded to the results of those tests until after randomization. For subjects assigned to the Early Amyloid PET Imaging arm, the managing physician will be blinded to the results of those tests until he or she has reviewed the results of the amyloid PET imaging.
• The patient has any life-threatening unstable medical disease or psychiatric condition that could lead to difficulty in complying with the protocol.
• The patient is currently receiving an investigational pharmaceutical product or has participated in a clinical trial with an investigational pharmaceutical product within 30 days prior to screening, and/or was administered a radiopharmaceutical within 10 radioactive half-lives prior to study drug administration in this study.
• The patient is a woman who is pregnant, planning to become pregnant, or lactating.
|E.5 End points
|Primary end point(s)
|The difference, at 12 weeks after baseline, between the Early Amyloid PET Imaging arm and the Late Amyloid PET Imaging arm in the proportion of patients for whom the managing physician has made an aetiologic diagnosis with very high confidence (≥90%). Diagnostic confidence, which is the managing physician’s confidence that the diagnosis is correct, will be measured with a visual analogue scale (VAS) from 0% (no confidence) to 100% (full confidence).
|Timepoint(s) of evaluation of this end point
|At 12 weeks after Baseline
|Secondary end point(s)
|Diagnosis and Confidence
• The difference between the Early Amyloid PET Imaging arm and the Late Amyloid PET Imaging arm in the time (from baseline) to communicate to the patient an aetiologic diagnosis with very high confidence (≥90%).
• ‘The changes in the managing physician’s aetiologic diagnosis at T3 vs T2 vs T1 in each arm.
• The changes in the managing physician’s diagnostic confidence at T3 vs T2 vs T1 vs T0 in the Early Amyloid PET Imaging arm vs the Late Amyloid PET Imaging arm.
• The managing physician’s estimate of the likelihood that the patient’s symptoms are due to AD at T3 vs T2 vs T1 vs T0 in the Early Amyloid PET Imaging arm vs the Late Amyloid PET Imaging arm.
• Changes over calendar time in the placement of amyloid PET imaging in the patient workup for subjects in the Free Choice Amyloid PET Imaging arm.
• The difference between arms (Early Amyloid PET Imaging arm, the Late Amyloid PET Imaging arm, or the Free Choice Amyloid PET Imaging arm) in the number of patients randomised to disease-modifying drug (DMD) or any other AD clinical trial at T2.
• The difference between the Early Amyloid PET Imaging arm and the Late Amyloid PET Imaging arm in number of subjects with changes in the management plan (changes in or start of a new program or pharmacologic treatment) at T1 vs T2 vs T3.
• Health Economics and Outcomes Research (HEOR) The impact on patient-related outcomes (cognition, anxiety, depression, coping skills, and quality of life) at T3 vs T2 vs T0 in each arm
• The difference in the cost of diagnostic workup to the aetiologic diagnosis with very high confidence (≥90%) in the Early Amyloid PET Imaging arm vs the Late Amyloid PET Imaging arm. (In those centres where the subjects in the Early Amyloid PET Imaging arm receive a diagnostic workup in addition to clinical evaluation before baseline, the relative costs will not be considered if the results of those exams are not known by the managing physician before the managing physician makes the aetiologic diagnosis.)
• Differences in the use of medical resources (not limited to diagnostic procedures, tests, visits, and hospitalisations) and programs between Early Amyloid PET Imaging and Late Amyloid PET Imaging arms.
• The number of patients who withdraw from the study and the reasons for withdrawal.
Imaging Results Assessment
• Descriptive analysis of local visual assessment results
• Mean values of quantitative image assessments (composite cortical standardised uptake value ratios [SUVR] and converted to the centiloid scale) across amyloid PET tracers and by diagnostic subgroup.
• The composite cortical quantitative uptake (SUVR and SUVR converted to the centiloid scale) vs visual reading interpretation
• For each of the amyloid PET tracers, the differences in regional quantitative uptake between diagnostic strata.
For subjects in the Early Amyloid PET Imaging arm who have a second amyloid PET scan:
• The longitudinal development of quantitative image assessments (regional and composite cortical SUVR and SUVR converted to the centiloid scale)
• The difference in amyloid load, as indicated by quantitative image assessments, between the first and the second amyloid PET scan
|Timepoint(s) of evaluation of this end point
|The timepoints are defined as follows: T0 = baseline, T1 = 12 weeks after T0, T2 = 6 months (±14 days) after T0, T3 = 13 months (±4 weeks) after T0; T4 = ≤28 days after the second scan, which will be approximately 18 months after T0. (All time points are calculated relative to baseline.)
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days