This study (AMYPAD Diagnostic and Patient Management Study) will determine in a real-life clinical setting for whom diagnostic amyloid PET imaging is appropriate, when this is best performed, and how the resulting information is influencing…
ID
Source
Brief title
Condition
- Encephalopathies
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference, at 12 weeks after baseline, between the Early Amyloid PET arm
and the Late Amyloid PET arm in the proportion of patients for whom the
managing physician has made an etiologic diagnosis with very high confidence
(*90%). Diagnostic confidence will be measured with a visual analogue scale
(VAS) ranging from 0% (no confidence) to 100% (full confidence).
Secondary outcome
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 12-18 months after T0. (All time
points are calculated relative to baseline.)
Diagnosis and Confidence
* The difference between the Early Amyloid PET arm and the Late Amyloid PET arm
in the time (from baseline) to communicate a very-high-confidence (*90%)
etiologic diagnosis to the patient.
* Change of etiologic diagnosis and incremental diagnostic confidence between
Baseline visit (T0) and T1 in each arm.
* Changes in the managing physician*s etiologic diagnosis at T3 vs T2 vs T1 in
each arm.
* Changes in the managing physician*s diagnostic confidence at T3 vs T2 vs T1
vs T0 in the Early Amyloid PET arm vs the Late Amyloid PET 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 arm vs
the Late Amyloid PET arm.
* Changes over calendar time in the placement of amyloid PET imaging in the
patient workup for participants in the Free Choice arm.
Patient Management
* The difference between arms (Early Amyloid PET arm, the Late Amyloid PET arm,
or the Free Choice 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 arm and the Late Amyloid PET arm
in number of participants 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
* 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 etiologic diagnosis
with very high confidence (*90%) in the Early Amyloid PET arm vs the Late
Amyloid PET arm.
* Differences in the use of medical resources (not limited to diagnostic
procedures, tests, visits, and hospitalisations) and programs between Early
Amyloid PET and Late Amyloid PET arms.
* The number of patients who withdraw from the study.
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 participants in the Early Amyloid PET arm who have a second amyloid PET
scan:
* The shift from amyloid positive to amyloid negative, and vice versa.
* The difference in amyloid load, as indicated by quantitative image
assessments, between the first and the second amyloid PET scan
Background summary
Alzheimer*s disease (AD) is the most common cause of cognitive impairment and
dementia and represents over 60% of all dementia cases. The key
neuropathological hallmarks of AD include the presence of extracellular
deposits of beta-amyloid (A*) peptides, intraneuronal neurofibrillary tangles,
and the predominance of neocortical neuronal degeneration. However, despite a
clinical assessment, AD is often not recognised, particularly in the early
stages or if mixed pathology is present and diagnosis based on clinical
criteria alone is difficult. In fact, it is estimated that around 50% of
diagnoses in persons presenting with objective cognitive impairment are
incorrect. Most commonly, the impairment is attributed to Alzheimer disease.
The percentage of incorrect diagnoses is still substantial even in more
advanced stages of the disease * comparisons to a neuropathological standard of
truth reveal that up to one-third of patients are misdiagnosed. However,
beta-amyloid (A*) deposition is considered to be a necessary step on the path
toward development of Alzheimer*s disease (AD). Therefore, the depiction of
brain A* in vivo can improve an early diagnosis of AD, and, when recognised in
a pre-symptomatic population, it might provide an opportunity for secondary
prevention of dementia. As a consequence, understanding the value of positron
emission tomography (PET) imaging of A* provides a unique opportunity to
improve the diagnostic workup of patients suspected to have AD, as well as
their management. In addition, the value, timing, and appropriateness of
amyloid PET imaging in clinical practice need to be established to allow its
cost-effective implementation in the diagnosis process of cognitive decline and
dementia.
Study objective
This study (AMYPAD Diagnostic and Patient Management Study) will determine in a
real-life clinical setting for whom diagnostic amyloid PET imaging is
appropriate, when this is best performed, and how the resulting information is
influencing diagnostic confidence, patient management, and ultimately decision
trees and cost-effectiveness of dementia care.
Specifically, we will study 3 groups of patients presenting to memory clinics
with a cognitive impairment due to AD, specifically those with subjective
cognitive decline plus (SCD Plus), mild cognitive impairment (MCI), and
dementia, to determine when amyloid PET imaging helps to exclude AD aetiology
(negative predictive value) or conveys an increased risk of AD (positive
predictive value) vis-à-vis other information and evidence (clinical,
structural imaging, genetic, CSF). Ultimately, the AMYPAD Diagnostic and
Patient Management Study will deliver an encompassing diagnostic algorithm
allowing a cost-efficient implementation of amyloid PET imaging in the clinical
practice. We will study the impact of the information provided by amyloid PET
imaging beyond diagnosis by determining the impact on patient management and
health resource utilisation, both in the current era of symptomatic treatment
and in the context of potentially effective disease-modifying therapies aimed
at lowering A* in the brain. Furthermore, we will determine if our diagnostic
algorithm is cost-effective from a health care perspective through providing
the input of economic modelling, in the context of the current regulatory
perspective.
Study design
This is a phase 4 multicentre, open-label study of amyloid PET imaging of
participants who have one of the following syndromic diagnoses: SCD-plus, MCI,
or dementia where AD is in the differential diagnosis.
The baseline visit must take place within 14 days after the screening visit and
can be combined with the screening visit. At baseline, the investigator will
record the syndromic diagnosis made by the managing physician, the managing
physician*s confidence in that diagnosis, and the managing physician*s estimate
of the likelihood that the patient*s symptoms are due to AD. (According to
[Johnson et al, 2013], the managing physician is a dementia expert trained and
board-certified in neurology, psychiatry, or geriatric medicine who devotes a
substantial proportion [at least 25%] of patient contact time to the evaluation
and care of adult acquired cognitive impairment or dementia.). The investigator
and the managing physician may be but do not have to be the same person.
Participants will be stratified by syndromic diagnosis (SCD-plus, MCI, or
dementia) and then randomly assigned (1:1:1) to 1 of 3 arms:
* Early Amyloid PET Arm: Participants will undergo amyloid PET imaging within 4
weeks after the baseline visit. The PET imaging must be performed before any
other diagnostic workup, and the results of the scan must be communicated to
the managing physician as soon as available and before the managing physician
receives the results of any other diagnostic workup. Early Amyloid PET arm
participants canl undergo a second amyloid PET scan at 12-18 months after the
initial scan. Amyloid load will be defined on the basis of a combination of
visual reading and quantitation. The results of the second amyloid PET scan
will not be provided to the managing physician and will not be used for
clinical purposes.
* Late Amyloid PET Arm: Participants will undergo amyloid PET imaging at 8
months (±8 weeks) after baseline.
* Free Choice Arm: The managing physician will decide whether the participant
undergoes amyloid PET imaging. The imaging can be done at any time within 12
months after baseline.
The visits and timepoints are defined as follows: T0 = baseline, T1 = 12 weeks
after T0, T2 = 6 months (±14 days) afterT0, T 3 = 13 months (±4 weeks) afterT0,
T4 = *28 days after the second PET scan, which will be done 12-18 months
after T0 zal (all visits and timepoints are relative to the baseline visit).
T3 and T4 are optional (if applicable).
Intervention
The intervention in this study consists of the addition of amyloid PET scanning
to the diagnostic process. Amyloid PET imaging will be conducted at the local
sites and read visually, and will not be considered a separate clinical visit.
The study will comprise the following clinical visits and timepoints:
* A baseline clinical visit (Visit 0 [V0] at Time 0 [T0]), within 14 days after
screening
* A timepoint 12 weeks after baseline (T1); no clinic visit is required at that
time
* A clinical visit at 6 months ±14 days (V1 or T2), and
* A clinical visit at 13 months ±4 weeks (V2 or T3)
At T1, the investigator will review the result communicated by the managing
physician (if the investigator and the managing physician are not the same
person) and record the etiologic diagnosis made by the managing physician, rate
the managing physician*s diagnostic confidence (0% to 100%, visual analogue
scale [VAS]) as well as the managing physician*s estimate of the likelihood
that the patient*s symptoms are due to AD (0% to 100%, VAS), and record the
effective date of the managing physician*s etiologic diagnosis and management
plan. This does not need to be a clinical visit.
At the baseline visit, all participants will receive a diary/questionnaire to
collect information on the use of medical resources.
Study burden and risks
Risks associated with participation in this study are related to:
- radiation exposure
- idiosyncratic reaction to the radiotracer injection
- placement of the intra-venous catheter
- discomfort during the PET scan
- incidental findings
- potentially confronting questionnaires related to anxiety and depression
feelings
- potential disclosure of amyloid PET results which may result in elevated
levels of anxiety and stress
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Listed location countries
Age
Inclusion criteria
* The patient can be of any sex, gender, race, or ethnicity.
* SCD-Plus patients must be 60 to 85 years of age
* Patients with MCI or dementia must be 50 to 85 years of age.
* 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 managing physician must feel that knowledge of amyloid status may
increase diagnostic
confidence or alter diagnosis and management.
o Patients should not have known amyloid status prior to randomization, * The
patient must satisfy the diagnostic criteria for one of the following:
o SCD-Plus
o MCI
o Dementia, where AD is in the differential diagnosis, * The patient has
undergone a dementia blood workup or will have one before amyloid PET.
* The patient has an MRI and/or CT scan or will undergo one before amyloid PET.
* The patient can complete all clinical visits according to the protocol.
* The patient can tolerate a 20-minute amyloid PET scan.
* The patient provides informed consent for study participation and data source
verification. In case the patient is randomized to the Early Amyloid PET arm, a
new informed consent should be signed before the second imaging session.
* If the patient has dementia, a study partner is available for the duration of
the protocol.
Exclusion criteria
Patient must be excluded if they meet any one of the following criteria:
* The patient has another confirmed condition that can fully account for the
cognitive impairment, including but not limited to psychiatric disorders
(schizophrenia, mood disorders, bipolar disorder and personality disorders;
neuroinflammatory, neuroinfective, or neurodegenerative diseases; multiple
sclerosis; genetic disorders; HIV; brain injuries; neurosurgery aftereffects;
major depressive episode; schizoaffective disorder; delusional disorder;
delirium). Patients with long-known, stabilized psychiatric or other brain
conditions that cannot fully account for the cognitive impairment may be
included in the study
* The patient comes to observation for reasons other than diagnosis (disability
assessment for social aids, cognitive assessment for driving license, etc.)
* The patient had a previous A* imaging scan and/or has had other AD biomarker
workup
(fluorodeoxyglucose [FDG]-PET and/or cerebrospinal fluid [CSF] analysis) prior
to screening. In some centres, the patient may receive a diagnostic workup
before screening. These patients can be enrolled if the investigator is blind
to the results until after randomization.
* The patient has a life-threatening or unstable medical disease, or a
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. Pregnancy status of a woman with childbearing potential will be
carried out before the PET scan. A woman is considered of childbearing
potential (WOCBP), i.e. fertile, following menarche and until becoming
post-menopausal unless permanently sterile (www.hma.eu/ctfg.html,
Recommendations related to contraception and pregnancy testing in clinical
trials, September 2014).
* The patient is employed at the research department or memory clinic, is
directly involved with the study, or is a family relative from any department
personnel (i.e. partner, older child, sibling, biological or legal
representative).
* Any of the contraindications as registered for the study drug used is
applicable to the subject. Any of the warnings or precautions as registered for
the IMP used is applicable to the subject, unless a risk-benefit assessment is
favorable as per the judgement of the sponsor.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002527-21-NL |
| CCMO | NL64423.029.17 |