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Molecular Imaging of Primary Amyloid Cardiomyopathy (MICA)

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ClinicalTrials.gov Identifier: NCT02641145
Recruitment Status : Recruiting
First Posted : December 29, 2015
Last Update Posted : September 12, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
American Heart Association
Information provided by (Responsible Party):
Sharmila Dorbala, MBBS, Brigham and Women's Hospital

Brief Summary:
Cardiac amyloidosis is a major cause of early treatment-related death and poor overall survival in individuals with systemic light chain amyloidosis. This project will develop a novel approach to visualize cardiac amyloid deposits using advanced imaging methods. The long-term goal of this work is to identify the mechanisms of cardiac dysfunction, in order to guide the development of novel life-saving treatments.

Condition or disease Intervention/treatment Phase
Amyloidosis, Primary Cardiomyopathy Radiation: F-18 florbetapir/C-11 acetate PET Device: MRI Radiation: N-13 ammonia PET Not Applicable

Detailed Description:
Primary light chain amyloidosis (AL) is the most common systemic amyloidosis, resulting from a plasma cell dyscrasia, a hematological malignancy. It causes a restrictive cardiomyopathy (AL-CMP) in over 70% of individuals. AL-CMP is as lethal as stage 4 lung cancer and more lethal than any other form of restrictive heart disease; if untreated, the mortality rate is 50% within 18 months. Moreover, myocardial dysfunction, the hallmark of AL-CMP, significantly increases early treatment related mortality, predominantly cardiovascular death, and is a powerful predictor of poor long-term survival. Two potentially treatable mechanisms underlie myocardial dysfunction—mechanical effects of amyloid and toxic effects from circulating light chain/ amyloid interactions—and predispose to heart failure, arrhythmias, and sudden death in individuals with AL-CMP. Until now, efforts to determine the mechanisms of AL-CMP have been hampered by a lack of animal models and the limitations of noninvasive techniques to directly image myocardial amyloid. A recent breakthrough, 18F-florbetapir PET/CT, has provided for the first time specific and quantitative imaging of myocardial amyloid including toxic amyloid protofibrils. Furthermore, we propose to investigate three pre-clinically proven pathways of light chain toxicity in humans—myocardial oxidative metabolism, oxidative stress, and coronary microvascular function. Our central hypotheses are that myocardial 18F-florbetapir retention is a biomarker for aggressiveness of AL-CMP and that effective chemotherapy will, by reducing circulating light chains, decrease aggressiveness of AL-CMP and improve oxidative stress, myocardial oxidative metabolism, microvascular function and contractile function, prior to an improvement in myocardial amyloid content. In Aim 1, we will quantify myocardial 18F-florbetapir retention as a marker of aggressive myocardial disease in individuals with AL-CMP and active plasma cell dyscrasia compared to control individuals with AL-CMP and long-term hematological remission. In Aim 2, we propose, using advanced imaging, to assess the effects of light chain reduction due to chemotherapy on myocardial structure, function, and metabolism and define the time course of these changes. Serial ECV and strain imaging by CMR, serum F2-isoprostanes and peroxynitrite levels, myocardial oxidative metabolism (Kmono) and coronary flow reserve by 11C-acetate PET, and 18F-florbetapir imaging will not only intricately characterize the myocardial substrate in AL-CMP, but also identify changes in response to therapy. The proposed studies offer the potential to transform our current understanding of AL-CMP as a restrictive heart disease caused by passive amyloid-related architectural damage to that of a more complex disorder resulting from both passive and aggressive factors. The results of these studies may form the foundation for drug discovery programs to prevent and cure AL-CMP.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 125 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Molecular Imaging of Primary Amyloid Cardiomyopathy
Study Start Date : April 2016
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Active AL cardiac amyloidosis
50 individuals with light chain systemic amyloidosis with active plasma cell dyscrasia and cardiac involvement will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of the heart at baseline, 6 months and 12 months after initiation of chemotherapy. 25 of these individuals will also undergo a N-13 ammonia PET scan of the heart following supine bicycle stress at baseline and at 6 months after initiation of chemotherapy.
Radiation: F-18 florbetapir/C-11 acetate PET
F-18 florbetapir PET scan, C-11 acetate PET scan

Device: MRI
Cardiac MRI with gadolinium contrast.

Radiation: N-13 ammonia PET
N-13 ammonia PET scan following supine bicycle stress.

Active Comparator: Remission AL cardiac amyloidosis
25 individuals with light chain systemic amyloidosis with cardiac involvement and plasma cell dyscrasia in hematological remission (complete hematological remission or very good partial response-differential free light chain (dFLC)<40 mg/dL for > 1 year prior to enrollment) will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI scan of the heart at baseline.
Radiation: F-18 florbetapir/C-11 acetate PET
F-18 florbetapir PET scan, C-11 acetate PET scan

Device: MRI
Cardiac MRI with gadolinium contrast.

Experimental: Active AL Pre-CMP
25 individuals with light chain systemic amyloidosis with active plasma cell dyscrasia and without cardiac involvement will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of the heart at baseline. At 6 months they will undergo a research MRI of the heart and at 12 months they will have a clinical follow up. Subjects with contraindications to Cardiac MRI or gadolinium contrast may still be eligible for study participation.
Radiation: F-18 florbetapir/C-11 acetate PET
F-18 florbetapir PET scan, C-11 acetate PET scan

Device: MRI
Cardiac MRI with gadolinium contrast.

No Intervention: Multiple Myeloma Controls
25 individuals with diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria will undergo urine and blood testing only.
Experimental: Heart Failure
10 individuals with diagnosis of heart failure without amyloidosis by standard criteria.
Radiation: F-18 florbetapir/C-11 acetate PET
F-18 florbetapir PET scan, C-11 acetate PET scan

Device: MRI
Cardiac MRI with gadolinium contrast.




Primary Outcome Measures :
  1. Change in F-18 florbetapir myocardial retention index from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
    quantitative measure of F-18 florbetapir uptake by the heart muscle

  2. Change in Serum oxidative stress markers from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
    serum F-2 isoprostane and peroxynitrite levels

  3. Change in Myocardial oxidative metabolism markers from baseline to 6 months [ Time Frame: Baseline and 6 months ]
    K mono and coronary flow reserve obtained by C-11 acetate PET/CT at rest and stress

  4. Change in Magnetic resonance imaging markers from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
    Extracellular volume index, T-1 mapping, late gadolinium enhancement, global strain, left ventricular mass


Secondary Outcome Measures :
  1. Change in Myocardial energy efficiency from baseline to 6 months [ Time Frame: Baseline and 6 months ]
    Myocardial energy efficiency, Kmono reserve, will be determined by C-11 acetate PET

  2. Light Chain Toxicity [ Time Frame: Baseline ]
    Study subject urine light chain's will be extracted and infused into zebrafish and isolated cardiomyocytes to study light chain toxicity



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Age > 18 years
  • Diagnosis of light chain amyloidosis by standard criteria (immunofixation of serum and urine, IgG free light chain (FLC) assay, a biopsy of fat pad/ bone marrow, or organ biopsy, followed by typing of the light chain using immunohistochemistry or immunogold assay with confirmation by Mass spectroscopy as needed)
  • Willing and able to provide consent
  • Additional inclusion criteria for the Remission AL-CMP: Hematological response defined as complete hematological remission or very good partial response-differential free light chain (dFLC)<40 mg/dL for > 1 year prior to enrollment
  • Additional inclusion criteria for the Active AL-CMP - exercise: Ability to perform supine bicycle exercise. Enrollment to this arm will stop after 25 subjects complete baseline and 6 months studies.
  • Additional inclusion criteria for the Active AL Pre-CMP - Normal left ventricular wall thickness (≤ 12 mm) and normal LVEF (≥55%) on echocardiography within 3 months or increased wall thickness with normal cardiac biomarker levels not meeting above definition.
  • Additional inclusion criteria for Control Multiple Myeloma subjects: diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria
  • Additional inclusion criteria for Control Heart Failure subjects: diagnosis of heart failure without amyloidosis by standard criteria

Exclusion Criteria:

  • Hemodynamic instability
  • Decompensated heart failure (unable to lie flat for 1 hour)
  • Concomitant non-ischemic non-amyloid heart disease (valvular heart disease or dilated cardiomyopathy)
  • Known obstructive epicardial coronary artery disease with stenosis > 50% in any single territory
  • Severe claustrophobia despite use of sedatives
  • Presence of MRI contraindications such as metallic implants (pacemaker or AICD) at the time of study enrollment
  • Significant renal dysfunction with estimated glomerular filtration rate < 30 ml/min/m2 within 14 days of each cardiac MRI study. Subjects who develop renal dysfunction over the course of the study, meeting criteria listed above, will be excluded from the cardiac MRI scan except for group D. Group D subjects with eGFR < 30 ml/min/1.73 m2 will undergo MRI without gadolinium contrast.
  • Subjects on dialysis will be excluded
  • Pregnant state. For women in child bearing age, a urine pregnancy test will be performed prior to the PET and the cardiac MRI studies
  • Documented allergy to F-18 florbetapir, C-11 acetate or gadolinium.
  • Additional exclusion criteria for the active AL-CMP subjects: Subjects unable to return to BWH for 6 and 12 month clinical evaluation
  • Additional exclusion criteria for active AL-CMP-exercise subjects: Inability to exercise or return to BWH for C-11 acetate PET/CT at baseline and 6 month clinical evaluations.
  • Additional exclusion criteria for active AL Pre-CMP- Inability to return to BWH 12 month clinical evaluation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02641145


Contacts
Contact: Sharmila Dorbala, MBBS 617-732-6290 sdorbala@partners.org

Locations
United States, Massachusetts
Brigham and Womens' Hospital Recruiting
Boston, Massachusetts, United States, 02421
Contact: Sharmila Dorbala       sdorbala@bwh.harvard.edu   
Principal Investigator: Sharmila Dorbala, MBBS         
Sponsors and Collaborators
Brigham and Women's Hospital
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
American Heart Association
Investigators
Principal Investigator: Sharmila Dorbala, MD Brigham and Women's Hospital (AHA and NIH Studies)
Principal Investigator: Rodney Falk, MD Brigham and Women's Hospital (NIH Study)
Principal Investigator: Ronglih Liao, PhD Brigham and Women's Hospital (AHA Study)

Responsible Party: Sharmila Dorbala, MBBS, Director, Nuclear Cardiology, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT02641145     History of Changes
Other Study ID Numbers: 2015P002477
1R01HL130563-01A1 ( U.S. NIH Grant/Contract )
First Posted: December 29, 2015    Key Record Dates
Last Update Posted: September 12, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Sharmila Dorbala, MBBS, Brigham and Women's Hospital:
amyloidosis
F-18 florbetapir
Positron emission tomography
cardiac magnetic resonance imaging

Additional relevant MeSH terms:
Cardiomyopathies
Amyloidosis
Heart Diseases
Cardiovascular Diseases
Proteostasis Deficiencies
Metabolic Diseases