Assessment of 18F-Florbetaben Whole-body PET for the Detection of Cardiac and Extracardiac Sites of Amyloid Deposits (CAPRI)

• Sponsor: Central Hospital, Nancy, France
• Information provided by (Responsible Party): Central Hospital, Nancy, France

Study Description

Brief Summary:

Although being classified as a rare disease, cardiac amyloidosis constitutes an increasing cause of heart failure, which is often overlooked and thus poorly managed. Amyloidosis involves deposits of light chain immunoglobulins in the AL type, but it may also be of a hereditary type in mutated transthyretin amyloidosis (ATTRm) or of a senile type in wildtype transthyretin forms (ATTRwt).

Myocardial biopsy remains a gold standard for definitive diagnosis but it is a traumatic technique which only provides information on a limited number of sampled sites.

Useful but not fully specific signs of cardiac amyloidosis may also be provided by Magnetic Resonance Imaging or MRI (delayed retention imaging) and echocardiography (longitudinal strain pattern).

Notwithstanding the above, relatively specific markers of amyloid plaques are now available in Positron Emission Tomography (PET). These markers are primarily fluorinated tracers which have been developed for the diagnosis of Alzheimer's disease. Two of these have already been the subject of feasibility studies in the setting of cardiac amyloidosis diagnosis, on a maximum of 10 amyloidosis patients but with very favorable results.

The hypothesis is that one of these two tracers, Florbetaben labelled with Fluorine-18-Florbetaben (18F-Florbetaben) used in the study, has sufficiently strong and prolonged binding kinetics at the level of the amyloid plaques to allow: (i) achieving whole-body PET recordings and thus, (ii) identifying not only cardiac amyloidosis but also extracardiac binding sites, particularly those readily accessible to biopsy sampling. This hypothesis has been strengthened by a recent case report illustrating the ability of whole-body florbetaben-PET to image not only cardiac but also extra-cardiac sites of amyloid deposits (Clin Nucl Med. 2017;42(1):50-3).

Condition or disease	Intervention/treatment	Phase
Cardiac Amyloidosis	Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging	Phase 3

Detailed Description:

In addition, distinctive imaging patterns pointing to amyloidosis may also be documented by other imaging techniques although insufficiently specific (e.g. decreased cardiac uptake of MIBG, evocative pattern of delayed retention at Magnetic Resonance Imaging (MRI) or at strain echocardiography. Specific markers of amyloid plaques have been developed for the diagnosis of Alzheimer's disease and were initially labeled with carbon-11 and more recently, with fluor-18. Most of these markers have already been the subject of feasibility studies on limited numbers of amyloidosis patients (max 10) but with favorable results. In a previous pilot study, one of these tracers, the 18F-Florbetaben used in the present study-protocol, exhibited particularly slow kinetics, with differences in cardiac uptake between patients and controls still being documented as late as 80-min following injection. This uptake was also found to be somewhat lower in the 5 ATTR patients comparatively to the 5 AL patients (Low WP and al, J Nucl Med 2016).

It may be hypothesized that 18F-Florbetaben has sufficiently slow and prolonged binding kinetics at the level of the amyloid plaques to allow: (i) achieving whole-body PET recordings with current recording times of 20 to 30 min and thus, (ii) identifying not only cardiac amyloidosis but also extracardiac binding sites, particularly those readily accessible to biopsy sampling. This hypothesis has just been strengthened by a recent case report, published by investigators involved in the present project and illustrating the ability of whole-body 18F-Florbetaben-PET to image not only cardiac but also various extracardiac sites of amyloid deposits (D'Estanque E. and al, Clin Nucl Med 2017).

The proposed study would be the first in which the sample size would be sufficient to provide a credible assessment of the ability of PET, using an amyloid plaque tracer, to identify cardiac amyloidosis and with a possible separate analysis of ATTR and AL forms. Moreover, it would also constitute the first study involving an extensive use of whole-body PET imaging to assess the benefit of amyloidosis detection, not only at the cardiac level, but also at peripheral sites, especially those accessible for biopsy (tongue, rectum, salivary glands, carpal tunnel, liver, subcutaneous tissue, thyroid,...).

Being able to confirm or invalidate the diagnosis of cardiac amyloidosis in a non-invasive manner and by guiding biopsy sampling to the most active extracardiac sites would be a major step forward for these patients whose diagnosis is most often established too late, i.e. at an advanced stage of heart failure.

In the longer term,18F-Florbetaben whole-body PET could be helpful for the non-invasive monitoring of the evolution of cardiac as well as extracardiac sites of amyloid deposits under dedicated specific treatments (chemotherapies in AL forms and specific treatments currently under investigation for the AL forms). Such monitoring is still impossible today.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	119 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Assessment of 18F-Florbetaben Whole-body PET Imaging for the Comprehensive Detection of Cardiac and Extracardiac Sites of Amyloid Deposits
Estimated Study Start Date :	June 20, 2019
Estimated Primary Completion Date :	June 20, 2021
Estimated Study Completion Date :	August 20, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: ATTR amyloidosis patients; Intervention by this arm: PET with injection of Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy	Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging; PET with Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy for the three arm; Other Names: bone scintigraphy; blood and urine sampling for protein electrophoresis
Experimental: AL amyloidosis patients; Intervention by this arm: PET with injection of Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy	Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging; PET with Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy for the three arm; Other Names: bone scintigraphy; blood and urine sampling for protein electrophoresis
Active Comparator: control subjects; Intervention by this arm: PET with injection of Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy. Control subjects are patients with left ventricular hypertrophy	Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging; PET with Neuraceq 300MBq/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy for the three arm; Other Names: bone scintigraphy; blood and urine sampling for protein electrophoresis

Outcome Measures

Primary Outcome Measures :

1. Definitive diagnosis of cardiac ATTR- or AL-amyloidosis upon current diagnostic standard (including cardiac or extracardiac biopsies), [ Time Frame: upon 24 months ]
   The diagnosis will be made with standard parameters (including cardiac or extracardiac biopsies), Importantly, a " control " population, including patients with left ventricular hypertrophy definitively unrelated to amyloidosis (even for low to mild forms) will be added for the analysis (this hypertrophy is mandatory for reaching a comparable partial volume effect than with amyloidosis patients when recording myocardial PET activity).

Secondary Outcome Measures :

1. Identical to the primary endpoint, although the analyses will be planned separately for AL- and ATTR-amyloidosis. [ Time Frame: upon 24 months ]
   The diagnosis will be made with standard parameters (including cardiac or extracardiac biopsies), Importantly, a " control " population, including patients with left ventricular hypertrophy definitively unrelated to amyloidosis (even for low to mild forms) will be added for the analysis (this hypertrophy is mandatory for reaching a comparable partial volume effect than with amyloidosis patients when recording myocardial PET activity).
2. Areas of abnormal (18)F-florbetaben uptake will be sought on the whole-body, especially in the extracardiac sites that are the most likely to present amyloid deposits, and particularly those most accessible to biopsy sampling [ Time Frame: upon 24 months ]
   the biopsy were made on the most accessible sites (tongue, rectum, submandibular glands, carpal tunnel, liver, thyroid and subcutaneous tissues etc.). This uptake will be quantified with SUV/TBR values within dedicated areas of interest and comparatively between case- and control-subjects.
3. Comparative analysis in patients and controls of the evolution all along the 60-min post-injection period [ Time Frame: upon 24 month ]
   the comparison of the analysis will be made with myocardial Standardized Uptake Values (SUV) where the measured activities are expressed relative to the injected activity and to patient's body weight (in g)
4. Comparative analysis in patients and controls of the evolution all along the 60-min post-injection period [ Time Frame: upon 24 month ]
   the comparison of the analysis will be made with myocardial tissue-to-background ratios (TBR) where the activities measured in SUV will be expressed relative to a mean blood background activity.
5. Comparative analysis in patients and controls of the evolution all along the 60-min post-injection period [ Time Frame: upon 24 month ]
   the comparison of the analysis will be made with a myocardial retention index where the myocardial SUVmean values will be expressed as a ratio with the integral of the blood time-activity curve at each time point.
6. The rates of (18)F-florbetaben whole-body PET being positive for cardiac amyloidosis [ Time Frame: upon 24 month ]
   it will be specifically determined in patients with positive bone scintigraphy (≥ mild cardiac uptake) and/or a positive MRI

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• For all study participants

  1. Person affiliated to or beneficiary of, a social security plan
  2. Person informed about study organization and having signed the informed consent

• For ATTR amyloidosis patients:

  1. left ventricular concentric hypertrophy with a diastolic septal thickness ≥ 15 mm at echography (as defined by the current distribution of this parameter in the ATTR patients involved in a French national cohort of the Henri Mondor Hospital),
  2. clearly positive bone scan (> mild cardiac uptake) and/or concordant results at pathology of cardiac or extra-cardiac sites (Congo red-positive deposits under crossed polarized light and immunohistochemical staining for transthyretin).

• For AL amyloidosis patients:

  1. left ventricular concentric hypertrophy with a diastolic septal thickness ≥ 13 mm at echography (as defined by the current distribution of this parameter in the AL patients involved in the French national cohort of the Henri Mondor Hospital),
  2. significant cardiac disease evidenced by an increase in plasma NT-ProBNP (or BNP) and/or in troponin T (or I), corresponding to a Mayo clinic score ≥ 2 ,
  3. concordant results at pathology of cardiac or extra-cardiac sites (Congo red-positive deposits under crossed polarized light and immunohistochemical staining for κ and λ immunoglobulin light chains).

• For control subjects:

  1. History of surgical or Transcatheter Aortic Valve Implantation (TAVI)treatment of aortic stenosis
  2. Matching with amyloidosis patients according to gender and age (± 5 years).
  3. Cardiac hypertrophy with a diastolic septal thickness ≥ 15 mm at echography when matching with an ATTR patient and ≥ 13 mm when matching with an AL patient.

Exclusion Criteria:

1. Known allergy to the active substance and to any excipient for 18F-Florbetaben or for the bone scintigraphy radiotracer (99mTc-MDP)
2. Pregnancy, breastfeeding and woman of childbearing age without effective contraception

3. Person referred in articles L.1121-5 to L.1121-8 and L.1122-2 of the Public Health Code:

   • Pregnant, parturient or breastfeeding woman
   • Person deprived of liberty for judicial or administrative decision
   • Person under psychiatric care
   • Person admitted to health or social institution for other reasons than research
   • Minor person (non-emancipated)
   • Adult person under legal protection (any form of public guardianship)
   • Adult person incapable of giving consent and not under legal protection
4. No obvious cause of cardiac disease except for mild to moderate hypertension in all study subjects, for cardiac amyloidosis in the amyloidosis groups and for aortic stenosis in the control group
5. Impossibility of performing 18F-Florbetaben PET (agitated, confused patient, etc.).
6. Sever left ventricular dysfunction with an ejection fraction ≤ 35%
7. Severe hepatic or renal failure.
8. For control patients only: monoclonal gammopathy on a previous protein electrophoresis or ≥ mild cardiac uptake on a previous bone scintigraphy.

Contacts and Locations

Contacts

Layout table for location contacts

Contact: Pierre-Yves PM MARIE, MD,PhD	03 83 15 39 09	py.marie@chru-nancy.fr
Contact: Véronique VR ROCH, MSc	03 83 15 42 76	v.roch@chru-nancy.fr

Locations

Layout table for location information

France
Chru Nancy	Not yet recruiting
Nancy, France, 54000
Contact: Véronique ROCH 00 33 83 15 42 76 v.roch@chru-nancy.fr
Principal Investigator: Antoine VERGER

Sponsors and Collaborators

Central Hospital, Nancy, France

Investigators

Layout table for investigator information

Principal Investigator:	Pierre-Yves PM MARIE, MD,PhD	CHRU de NANCY BRABOIS

More Information

Layout table for additonal information

Responsible Party:	Central Hospital, Nancy, France
ClinicalTrials.gov Identifier:	NCT03616496 History of Changes
Other Study ID Numbers:	2018-004054-24
First Posted:	August 6, 2018
Last Update Posted:	June 17, 2019
Last Verified:	June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Layout table for additional information

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Central Hospital, Nancy, France:

PET imaging; Cardiac Amyloidosis; Florbetaben; Heart failure; Cardiology

Additional relevant MeSH terms:

Layout table for MeSH terms

Amyloidosis; Plaque, Amyloid; Proteostasis Deficiencies; Metabolic Diseases; Pathological Conditions, Anatomical