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

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ClinicalTrials.gov Identifier: NCT03616496
Recruitment Status : Not yet recruiting
First Posted : August 6, 2018
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
Central Hospital, Nancy, France

Tracking Information
First Submitted Date  ICMJE July 27, 2018
First Posted Date  ICMJE August 6, 2018
Last Update Posted Date September 4, 2019
Estimated Study Start Date  ICMJE September 20, 2019
Estimated Primary Completion Date September 20, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 2, 2019)
  • 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).
  • 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 Standardized Uptake Values (SUV)/Target-to-Background Ratio (TBR) values within dedicated areas of interest and comparatively between case- and control-subjects.
  • 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)
  • 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.
  • 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 mean standardized uptake values (SUVmean) will be expressed as a ratio with the integral of the blood time-activity curve at each time point.
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
  • 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).
  • 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.
  • 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)
  • 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.
  • 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.
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessment of 18F-Florbetaben Whole-body PET for the Detection of Cardiac and Extracardiac Sites of Amyloid Deposits
Official Title  ICMJE Assessment of 18F-Florbetaben Whole-body PET Imaging for the Comprehensive Detection of Cardiac and Extracardiac Sites of Amyloid Deposits
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 immunoglobulin light chain amyloidosis (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).

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 metaiodobenzylguanidine (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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cardiac Amyloidosis
Intervention  ICMJE 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
Study Arms  ICMJE
  • Experimental: ATTR amyloidosis patients
    Intervention by this arm: PET with injection of Neuraceq 300 Mega Becquerel (MBq)/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy
    Intervention: Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging
  • Experimental: AL amyloidosis patients
    Intervention by this arm: PET with injection of Neuraceq 300 Mega Becquerel/ml, blood and urine sampling for protein electrophoresis, bone scintigraphy
    Intervention: Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging
  • 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

    Intervention: Drug: Neuraceq 300MBq/mL Solution for Injection for PET imaging
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: August 3, 2018)
119
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 20, 2021
Estimated Primary Completion Date September 20, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 N-Terminal 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03616496
Other Study ID Numbers  ICMJE 2018-004054-24
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Central Hospital, Nancy, France
Study Sponsor  ICMJE Central Hospital, Nancy, France
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Pierre-Yves PM MARIE, MD,PhD CHRU de NANCY BRABOIS
PRS Account Central Hospital, Nancy, France
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP