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Molecular Imaging of Primary Amyloid Cardiomyopathy (MICA)

Primary Purpose

Amyloidosis, Primary, Cardiomyopathy

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

F-18 florbetapir/C-11 acetate PET

MRI

N-13 ammonia PET

About this trial

This is an interventional diagnostic trial for Amyloidosis, Primary focused on measuring amyloidosis, F-18 florbetapir, Positron emission tomography, cardiac magnetic resonance imaging

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)
- For subjects traveling from out of town referred for systemic AL therapy based on clinical evaluation and laboratory testing, but, pending biopsy results, study enrollment and procedures may begin before official confirmation of biopsy results. If biopsy is negative for AL amyloidosis, subject will be considered a screen failure. There will be no more than 10 subjects who fall under this screen failure for the duration of the study.
- Subjects with localized amyloid deposition and non-systemic AL disease will be eligible for enrollment in group D.
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 36 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
Additional inclusion criteria for the active AL-CMP: Abnormal TnT 5th generation levels (>9 ng/L: Female, >14 ng/L: Male) or abnormal age appropriate N terminal pro-brain natriuretic peptide, NT-proBNP (abnormal values: <50 years: >450 pg/ml; 50-75 years:>900 pg/ml; >75 years: >1800 pg/ml)

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 ICD) at the time of study enrollment except for Control Heart Failure subjects. Control HF subjects with no devices, or, with strictly MR compatible devices will be eligible to undergo MRI.
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 control HF subjects. These 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.

Additional exclusion criteria for microbiota study: Documented hypertrophic cardiomyopathy, HIV or chronic viral hepatitis, documented inflammatory bowel disease, systemic antibiotics, antivirals, antifungals or antiparasitic agents within 6 months, unable to mail the stool sample in a timely manner, bowel surgery, colon cancer, received chemotherapy, and pregnancy.

Sites / Locations

Brigham and Womens' HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Experimental

No Intervention

Experimental

Arm Label

Active AL cardiac amyloidosis

Remission AL cardiac amyloidosis

Active AL Pre-CMP

Multiple Myeloma Controls

Heart Failure

Arm Description

75 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 blood of the heart, as well as the heavy metal analysis of the blood 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.

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 as well as a heavy metal analysis of the blood at baseline.

36 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, as well as a heavy metal analysis of the blood 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.

25 individuals with diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria will undergo urine and blood testing only.

10 individuals with diagnosis of heart failure without amyloidosis by standard criteria will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of the heart, as well as a heavy metal analysis of the blood at baseline..

Outcomes

Primary Outcome Measures

Change in F-18 florbetapir myocardial retention index from baseline to 6 months and 12 months

quantitative measure of F-18 florbetapir uptake by the heart muscle

Change in Serum oxidative stress markers from baseline to 6 months and 12 months

serum F-2 isoprostane and peroxynitrite levels

Change in Myocardial oxidative metabolism markers from baseline to 6 months

K mono and coronary flow reserve obtained by C-11 acetate PET/CT at rest and stress

Change in Magnetic resonance imaging markers from baseline to 6 months and 12 months

Extracellular volume index, T-1 mapping, late gadolinium enhancement, global strain, left ventricular mass

Secondary Outcome Measures

Change in Myocardial energy efficiency from baseline to 6 months

Myocardial energy efficiency, Kmono reserve, will be determined by C-11 acetate PET

Light Chain Toxicity

Study subject urine light chain's will be extracted and infused into zebrafish and isolated cardiomyocytes to study light chain toxicity

Understand the role of gut microbiota and heavy metals in the pathogenesis of AL Amyloidosis

This will be tested using machine learning methods with 16S rRNA sequencing of salivary and stool samples in a 40-patient cohort with AL-amyloidosis compared to healthy controls from the NIH funded human microbiome project (HMP).This will also be used to test if the gut microbiome affects amyloid formation using a transgenic mouse model of AL amyloidosis that expresses the human LC in the gut and develops amyloid in the stomach.

Full Information

NCT ID

NCT02641145

First Posted

December 22, 2015

Last Updated

July 25, 2023

Sponsor

Brigham and Women's Hospital

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), American Heart Association

1. Study Identification

Unique Protocol Identification Number

NCT02641145

Brief Title

Molecular Imaging of Primary Amyloid Cardiomyopathy

Acronym

MICA

Official Title

Molecular Imaging of Primary Amyloid Cardiomyopathy

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 1, 2016 (undefined)

Primary Completion Date

January 8, 2024 (Anticipated)

Study Completion Date

January 8, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Brigham and Women's Hospital

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), American Heart Association

4. Oversight

Data Monitoring Committee

5. Study Description

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.

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. Interactions of environmental factors, immunity, and host-related factors likely trigger AL-amyloidosis, but have not yet been explored. Changes in metal ions and gut microbiota may be causal, representing the integrated effects of all these factors, or may be the downstream effect of systemic amyloid deposition in the organ systems. A plethora of recent literature strongly support the role of microbiota in the pathogenesis of several diseases, suggesting that gut microbiota changes with age, influences heart failure (HF) outcomes, and plays a role in the formation of β-amyloid deposits in Alzheimer's disease. Importantly, alterations in lifestyle, diet, prebiotics, probiotics, or phenols and gut microbiota may represent therapeutic and preventative strategies in amyloid disease, but it has not been explored in AL-amyloidosis. We propose to study the role of salivary and gut microbiome in AL amyloidosis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyloidosis, Primary, Cardiomyopathy

Keywords

amyloidosis, F-18 florbetapir, Positron emission tomography, cardiac magnetic resonance imaging

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

171 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Active AL cardiac amyloidosis

Arm Type

Experimental

Arm Description

Arm Title

Remission AL cardiac amyloidosis

Arm Type

Active Comparator

Arm Description

Arm Title

Active AL Pre-CMP

Arm Type

Experimental

Arm Description

Arm Title

Multiple Myeloma Controls

Arm Type

No Intervention

Arm Description

25 individuals with diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria will undergo urine and blood testing only.

Arm Title

Heart Failure

Arm Type

Experimental

Arm Description

Intervention Type

Radiation

Intervention Name(s)

F-18 florbetapir/C-11 acetate PET

Intervention Description

F-18 florbetapir PET scan, C-11 acetate PET scan

Intervention Type

Device

Intervention Name(s)

MRI

Intervention Description

Cardiac MRI with gadolinium contrast.

Intervention Type

Radiation

Intervention Name(s)

N-13 ammonia PET

Intervention Description

N-13 ammonia PET scan following supine bicycle stress.

Primary Outcome Measure Information:

Title

Change in F-18 florbetapir myocardial retention index from baseline to 6 months and 12 months

Description

quantitative measure of F-18 florbetapir uptake by the heart muscle

Time Frame

Baseline, 6 and 12 months

Title

Change in Serum oxidative stress markers from baseline to 6 months and 12 months

Description

serum F-2 isoprostane and peroxynitrite levels

Time Frame

Baseline, 6 and 12 months

Title

Change in Myocardial oxidative metabolism markers from baseline to 6 months

Description

K mono and coronary flow reserve obtained by C-11 acetate PET/CT at rest and stress

Time Frame

Baseline and 6 months

Title

Change in Magnetic resonance imaging markers from baseline to 6 months and 12 months

Description

Extracellular volume index, T-1 mapping, late gadolinium enhancement, global strain, left ventricular mass

Time Frame

Baseline, 6 and 12 months

Secondary Outcome Measure Information:

Title

Change in Myocardial energy efficiency from baseline to 6 months

Description

Myocardial energy efficiency, Kmono reserve, will be determined by C-11 acetate PET

Time Frame

Baseline and 6 months

Title

Light Chain Toxicity

Description

Study subject urine light chain's will be extracted and infused into zebrafish and isolated cardiomyocytes to study light chain toxicity

Time Frame

Baseline

Title

Understand the role of gut microbiota and heavy metals in the pathogenesis of AL Amyloidosis

Description

Time Frame

Baseline

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility 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) For subjects traveling from out of town referred for systemic AL therapy based on clinical evaluation and laboratory testing, but, pending biopsy results, study enrollment and procedures may begin before official confirmation of biopsy results. If biopsy is negative for AL amyloidosis, subject will be considered a screen failure. There will be no more than 10 subjects who fall under this screen failure for the duration of the study. Subjects with localized amyloid deposition and non-systemic AL disease will be eligible for enrollment in group D. 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 36 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 Additional inclusion criteria for the active AL-CMP: Abnormal TnT 5th generation levels (>9 ng/L: Female, >14 ng/L: Male) or abnormal age appropriate N terminal pro-brain natriuretic peptide, NT-proBNP (abnormal values: <50 years: >450 pg/ml; 50-75 years:>900 pg/ml; >75 years: >1800 pg/ml) 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 ICD) at the time of study enrollment except for Control Heart Failure subjects. Control HF subjects with no devices, or, with strictly MR compatible devices will be eligible to undergo MRI. 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 control HF subjects. These 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. Additional exclusion criteria for microbiota study: Documented hypertrophic cardiomyopathy, HIV or chronic viral hepatitis, documented inflammatory bowel disease, systemic antibiotics, antivirals, antifungals or antiparasitic agents within 6 months, unable to mail the stool sample in a timely manner, bowel surgery, colon cancer, received chemotherapy, and pregnancy.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Sharmila Dorbala, MD, MPH

Phone

617-732-6290

sdorbala@partners.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sharmila Dorbala, MD

Organizational Affiliation

Brigham and Women's Hospital (AHA and NIH Studies)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Rodney Falk, MD

Organizational Affiliation

Brigham and Women's Hospital (NIH Study)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Ronglih Liao, PhD

Organizational Affiliation

Stanford School of Medicine (AHA Study)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham and Womens' Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02421

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sharmila Dorbala

sdorbala@bwh.harvard.edu

First Name & Middle Initial & Last Name & Degree

Sharmila Dorbala, MBBS

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

We do not have a plan to share individual participant data with other researchers

Citations:

PubMed Identifier

34922860

Citation

Cuddy SAM, Jerosch-Herold M, Falk RH, Kijewski MF, Singh V, Ruberg FL, Sanchorawala V, Landau H, Maurer MS, Yee AJ, Bianchi G, Di Carli MF, Liao R, Kwong RY, Dorbala S. Myocardial Composition in Light-Chain Cardiac Amyloidosis More Than 1 Year After Successful Therapy. JACC Cardiovasc Imaging. 2022 Apr;15(4):594-603. doi: 10.1016/j.jcmg.2021.09.032. Epub 2021 Dec 15.

Results Reference

derived

PubMed Identifier

32417333

Citation

Cuddy SAM, Bravo PE, Falk RH, El-Sady S, Kijewski MF, Park MA, Ruberg FL, Sanchorawala V, Landau H, Yee AJ, Bianchi G, Di Carli MF, Cheng SC, Jerosch-Herold M, Kwong RY, Liao R, Dorbala S. Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease? JACC Cardiovasc Imaging. 2020 Jun;13(6):1325-1336. doi: 10.1016/j.jcmg.2020.02.025. Epub 2020 May 13.

Results Reference

derived

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Molecular Imaging of Primary Amyloid Cardiomyopathy

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