Clinical trial NCT06120049: [18F]-MFBG Versus [123I]-MIBG and [18F]-PE2I in PD vs. MSA and DLB vs. AD
Official title: Prospective Head-to-head Comparison of Cardiac [18F]-MFBG PET Versus [123I]-MIBG SPECT in the Differentiation Between Parkinson's Disease and Multiple System Atrophy and Between Dementia With Lewy Bodies and Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Parkinson Disease
Dementia With Lewy Bodies
MSA - Multiple System Atrophy
Alzheimer Disease
Keywords: Parkinson Disease
Dementia with Lewy Bodies
MSA - Multiple System Atrophy
Alzheimer Disease
[18F]-MFBG
[18F]-PE2I
[123I]-MIBG
Positron emission tomography
PET
Single photon emission tomography
SPECT
Autonomic dysfunction
Cardiac innervation
Brain DAT
Dosimetry
Kinetic modelling
Differential diagnosis
Dementia
Parkinsonism
Nuclear imaging
Neurology
Movement disorders
Prospective
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: University Hospital, Ghent
name: Fund for Scientific Research, Flanders, Belgium
name: KU Leuven
name: Universitaire Ziekenhuizen KU Leuven
First posted: 2023-11-07
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective head-to-head comparison with 5 subject panels (healthy controls, Parkinson's disease, Multiple System Atrophy, Dementia with Lewy Bodies and Alzheimer's disease). The main study is a prospective diagnostic study in three cohorts (1/ CON, 2/ PD vs. MSA-P, 3/ DLB vs AD). The study in healthy controls is designated part 2. The study in patients is designated part 3. There is a seperate dosimetry study, designated as part 1.
Primary purpose: DIAGNOSTIC

Brief summary: Study goal:

The goal of this prospective head to head comparison is to evaluate the effectiveness of \[18F\]-MFBG PET in assessing cardiac innervation, comparing it with \[123I\]-MIBG SPECT The study's primary focus is on distinguishing between Parkinson's disease (PD) and multiple system atrophy (MSA), as well as between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).

Main questions:

* Feasibility: How well can \[18F\]-MFBG PET detect changes in myocardial uptake in PD and DLB compared to the expected normal values in healthy individuals and AD and MSA-P patients? How well can it differentiate between these groups based on the detected changes?
* Non-inferiority: Is \[18F\]-MFBG PET as accurate as \[123I\]-MIBG SPECT in distinguishing between PD and MSA-P, and between DLB and AD?

Participant requirements:

For the main study, participants will be required to visit the hospital for 3 or 4 appointments. During these visits, they will undergo a screening visit, MRI brain scan, a comprehensive neurological assessment, \[18F\]-PE2I PET, \[123I\]-MIBG SPECT, and \[18F\]-MFBG PET scans.

Additionally, a separate dosimetry study will be conducted, involving healthy subjects who will visit the hospital for a screening visit and undergo \[18F\]-MFBG PET scans.

Detailed description: Study Rationale:

This prospective study, to be conducted in two centers (UZ Leuven and UZ Gent), aims to validate cardiac \[18F\]-MFBG PET in distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA-P) and differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Both PD and DLB, caused by alpha-synuclein deposits (Lewy bodies), exhibit not only nigrostriatal dopaminergic deficits but also early peripheral changes in myocardial norepinephrine (NE) innervation. These defects can be visualized and quantified using NE transporter tracers. \[18F\]-MFBG was developed several years ago with high-yield production and has already been employed in multiple centers worldwide, mainly in the context of imaging neuroendocrine tumors. \[18F\]-MFBG offers logistical, technical, and pharmacological advantages, including faster scanning, high spatial resolution, and improved quantification compared to the existing method using \[123I\]-MIBG SPECT.

Participant Population:

The study will include 28 healthy volunteers (CON), of which 3 will participate in \[18F\]-MFBG PET dosimetry (part 1) and 25 in the main study for optimization/age-dependence of cardiac \[18F\]-MFBG parameters (part 2). In part 3, 40 PD, 15 MSA-P, 15 DLB, and 15 AD patients with biomarker-confirmed diagnoses will be included. Total: 113 subjects.

Intervention:

All subjects will undergo three examinations in the main work packages (parts 2 and 3) dynamic cardiac \[18F\]-MFBG PET, with dynamic \[123I\]-MIBG SPECT as a comparator, as well as cerebral \[18F\]-PE2I PET.

Endpoints:

Primary: Non-inferiority in discriminating populations using \[18F\]-MFBG; Secondary: effect size, relationship between myocardial uptake and cerebral dopamine active transporter (DAT) changes, autonomic dysfunction, regional myocardial variation.

Secondary:

1. Determine the effect size (ES) of the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB compared to \[123I\]-MIBG SPECT and \[123I\]-MIBG planar scintigraphy.
2. Identify any significant correlation between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and the reduction in \[18F\]-PE2I binding in early to moderate disease stages.
3. Assess the relationship between the reduction in myocardial uptake of \[18F\]-MFBG in PD and DLB and measures of autonomic dysfunction.
4. Examine the regional pattern of reduced \[18F\]-MFBG uptake in PD/DLB compared to controls, with an endpoint considered met if different regional segment scores are evident between PD/MSA-P or DLB/AD or subtypes of PD.

Eligibility criteria: Inclusion Criteria:

1. Healthy Controls:

   * Voluntary written informed consent.
   * Use of highly effective methods of birth control.
   * Age between 18 and 85 years.
   * Good health based on medical history, physical examination, clinical laboratory tests, and urinalysis.
   * No history or evidence of major neurological, internal, or psychiatric disorders.
   * Normal structural MRI scan for subjects \< 60 years or minor lesions for subjects \>= 60 years.
2. Parkinson's Disease:

   * Age 45-85 years.
   * Clinically established PD based on Movements Disorder Society diagnostic criteria.
   * Disease duration since onset of motor symptoms: 5 years or longer for one group and less than 5 years for another.
   * Previous abnormal \[18F\]-FE-PE2I PET or \[123I\]-FP-CIT SPECT scan.
   * Ability to understand the patient information brochure and provide written informed consent.
3. Multiple System Atrophy - Parkinsonian Variant:

   * Age 45-85 years.
   * Clinically established or clinically probable MSA-P based on MDS diagnostic criteria.
   * Previous abnormal \[18F\]-FE-PE2I PET or \[123I\]-FP-CIT SPECT scan.
   * Ability to understand the patient information brochure and provide written informed consent.
4. Dementia Due to Alzheimer's Disease:

   * Age 50-85 years.
   * Diagnosis of probable AD with evidence of the AD pathophysiological process.
   * Ability to understand the patient information brochure and provide written informed consent.
5. Dementia with Lewy Bodies:

   * Age 50-85 years.
   * Diagnosis of probable DLB.
   * Previous abnormal \[18F\]-FE-PE2I PET or \[123I\]-FP-CIT SPECT scan.
   * Ability to understand the patient information brochure and provide written informed consent.

Exclusion Criteria:

1. Healthy controls:

   * Major diseases that may interfere with the investigations.
   * Evidence of cognitive impairment.
   * History or evidence of psychiatric disease.
   * Use of illicit drugs or history of drug or alcohol abuse.
   * Chronic medication interfering with cardiac neuronal norepinephrine transporter (NET) or \[18F\]-FE-PE2I imaging.
   * Exposure to ionizing radiation \> 1 mSv in other research studies within the last 12 months.
   * Contraindication for MRI scanning.
   * Claustrophobia or inability to tolerate confinement during PET-MRI scanning.
   * Unwillingness to avoid strenuous physical activity.
   * Lack of understanding of the study procedures.
   * Pregnancy or breastfeeding.
   * Lack of agreement to communicate incidental findings to the general practitioner.
   * Abnormal Allen test or lidocaine hypersensitivity/allergy for subjects willing to undergo arterial sampling.
2. Parkinson's Disease:

   * Neuropsychiatric diseases other than PD.
   * Major internal medical comorbidity, especially diabetes or heart disease.
   * White matter lesion load on FLAIR Fazekas score 2 or higher or other relevant MRI abnormalities.
   * History of alcohol or drug abuse.
   * Previous participation in research studies involving ionizing radiation.
   * Contraindications for MR.
   * Claustrophobia or inability to tolerate confinement during PET scanning.
   * Unwillingness to avoid strenuous physical activity.
   * Lack of understanding of the study procedures.
   * Pregnancy or breastfeeding.
   * Lack of agreement to communicate incidental findings to the general practitioner.
   * Anticoagulant therapy.
3. Multiple System Atrophy - Parkinsonian Variant:

   * Same as for Parkinson's disease.
4. Dementia Due to Alzheimer's Disease:

   * Same as for Parkinson's disease.
5. Dementia with Lewy Bodies:

   * Same as for Parkinson's disease.

Primary outcomes:
measure: Difference in diagnostic accuracy between [18F]-MFBG and [I123]-MIBG
timeFrame: Diagnostic accuracy will be calculated when the scans of the PD and MSA panels have been completed and again when scanning of DLB and AD panels has been completed (estimated 3 years after study start).
Secondary outcomes:
measure: Effect size
timeFrame: Effect size will be calculated when all scans have been completed (estimated 3 years after study start).
measure: Relation to brain DAT
timeFrame: The relation to brain DAT will be calculated when the scans of PD, DLB and HC groups have been completed (estimated 3 years).
measure: Correlation of myocardial uptake of [18F]-MFBG to autonomic dysfunction
timeFrame: The relation to autonomic dysfunction will be calculated when the scans of PD and DLB patients have been completed (estimated 2 years after study start)..
measure: Utility of regional myocardial parameter variation
timeFrame: The regional myocardial parameter variation will be calculated when the scans of patient groups have been completed (estimated 3 years after study start).
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams-Brabant
city: Gent
country: Belgium
facility: UZ Ghent
Study officials:
affiliation: Professor at KULeuven, department head of nuclear medicine at UZ Leuven
name: Koen Van Laere
role: PRINCIPAL_INVESTIGATOR
References: