Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations (SCAN-MP)

• ClinicalTrials.gov Identifier: NCT03812172
• Recruitment Status: Recruiting
• First Posted: January 23, 2019
• Last Update Posted: July 26, 2021
• Sponsor: Mathew Maurer
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Boston Medical Center; Harlem Hospital Center; The Scripps Research Institute
• Information provided by (Responsible Party): Mathew Maurer, Columbia University

Study Description

Brief Summary:

In this study, the investigators will recruit a cohort of elderly Black and Hispanic patients with heart failure to define the number of patients who have cardiac amyloidosis by utilizing highly sensitive heart imaging and blood tests. The investigators will also explore differences in genetics and sex as they relate to heart failure disease progression in cardiac amyloidosis.

Condition or disease	Intervention/treatment
Amyloid Cardiomyopathy, Transthyretin-Related	Drug: 99mTc-PYP

Detailed Description:

Heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older Black and Hispanic Americans. ATTR cardiac amyloidosis (ATTR CA) is caused by myocardial deposition of misfolded transthyretin protein (TTR or prealbumin) and is classified by the genetics of TTR into wild-type (ATTRwt) or hereditary (hATTR or ATTRm). ATTR CA, irrespective of genotype, is an age-dependent, often unrecognized, mechanism underlying HFpEF. While hATTR CA results from point mutations that promote TTR misfolding and amyloid aggregation, factors that contribute to ATTRwt CA are not well defined. While previously thought to be untreatable, promising therapies that have been recently reported are most effective if administered early in disease course. Only a small proportion of individuals with wild-type TTR will develop ATTRwt CA, overwhelmingly reported in Caucasian males beyond age 60 years. However, as an autosomal protein, allele distribution is not sex specific. For hATTR, a substitution of isoleucine for valine (Val122Ile) is the most frequent TTR mutation in the US, observed exclusively in Black Americans with an allele frequency of 3.4%. But there are no data regarding the prevalence of ATTRwt CA in African Americans and no data for ATTR CA prevalence, irrespective of genotype, in the Hispanic population. One of the reasons for the knowledge deficit is the challenge of diagnosis. Endomyocardial biopsy, while nearly 100% sensitive and specific, is impractical as a screening test and genotyping alone of patients is insufficient to identify ATTR CA because wild-type patients develop disease. In this study, the investigators will use a highly accurate technique for ATTR CA identification using Tc99m-pyrophosphate (PYP) imaging that avoids the need for biopsy. Tc99m-PYP myocardial uptake can occur before echocardiographic or clinical changes, suggesting enhanced sensitivity. While studies using the technique have suggested that 10-15% of elderly hospitalized patients with HF may have ATTR CA, Tc99m-PYP has not been applied broadly in HF patients as a means to facilitate early diagnosis. In addition, the investigators will test the diagnostic accuracy of a point-of-care diagnostic tool that utilizes a novel biomarker, retinol binding protein 4 (RBP4), and an assay to measure TTR stability. The overall hypothesis is that a significant proportion of HF in elderly Blacks and Hispanics is caused ATTR CA. Using these non-invasive tests, the investigators will establish the prevalence of ATTR CA and explore the relationship between RBP4 concentration and TTR stability in a prospective cohort study of elderly Black and Hispanic Americans with HF.

Study Design

• Study Type: Observational
• Estimated Enrollment: 800 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Screening for Cardiac Amyloidosis Using Nuclear Cardiology for Minority Populations
• Actual Study Start Date: May 15, 2019
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Groups and Cohorts

Group/Cohort	Intervention/treatment
Blacks/Hispanics with Heart Failure; Blacks/Hispanics with heart failure due to transthyretin cardiac amyloidosis will be identified by 99mTc-PYP scintigraphy. Those with transthyretin cardiac amyloidosis will be further subtyped into those with a genetic cause (ATTRm) and those with a non-genetic cause (ATTRwt - wild type transthyretin cardiac amyloidosis).	Drug: 99mTc-PYP; 10 mCi of 99mTc-PYP will be administered intravenously and imaging will be performed after 1 hour.; Other Name: Technetium-99m-Pyrophosphate

Outcome Measures

Primary Outcome Measures :

1. Prevalence of Transthyretin Cardiac Amyloidosis in Caribbean Hispanics and Blacks with heart failure (HF) [ Time Frame: 5 years ]
   The prevalence of ATTR CA will be defined by the number of cases with significant myocardial retention of Tc-99 PYP including both ATTRwt and ATTRm CA as a percentage of total enrollment.

Secondary Outcome Measures :

1. Prevalence of ATTRwt and ATTRm in Blacks and Caribbean Hispanics [ Time Frame: 5 years ]
   Among subjects with ATTR-CA we will determine the prevalence of ATTRwt and ATTRm from the Val122Ile mutation in Blacks and Caribbean Hispanics
2. Sex distribution of ATTR cardiac amyloidosis [ Time Frame: 5 years ]
   The prevalence of ATTR cardiac amyloidosis will be calculated among men and women enrolled in this study
3. Disease progression in ATTRwt compared to ATTRm [ Time Frame: 5 years ]
   In the ATTR CA group alone, a composite time-to-first-event endpoint at 1-year of death, heart failure hospitalization, or 30% decline in 6-minute hall walk will be compared between ATTRwt and ATTRm subjects.
4. RBP4 in Urine [ Time Frame: 5 years ]
   Retinol binding protein 4 (RBB4) will be measured in urine.

Biospecimen Retention:   Samples With DNA

Participants in this study will provide samples of blood and urine which will be analyzed for specific biomarkers and stored for possible future research.

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Blacks and Caribbean Hispanics with heart failure not primarily due to ischemic heart disease or valvular disease.

Criteria

Inclusion Criteria:

1. Black or Hispanic of Caribbean origin.
2. Age ≥ 60 years.

3. Diagnosis of heart failure, confirmed by one of two methods:

   1. Modified criteria utilized by Rich et al. which include a history of acute pulmonary edema or the occurrence of at least two of the following that improved with diuretic therapy without another identifiable cause: dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema or exertional fatigue, and
   2. National Health and Nutrition Examination Survey (NHANES) congestive heart failure (CHF) criteria with a score ≥3.
4. Able to understand and sign the informed consent document after the nature of the study has been fully explained.

Exclusion Criteria:

1. Primary amyloidosis (AL) or secondary amyloidosis (AA).
2. Prior liver or heart transplantation.
3. Active malignancy or non-amyloid disease with expected survival of less than 1 year.
4. Heart failure, in the opinion of the investigator, primarily caused by either valve disease or ischemic heart disease.

Contacts and Locations

Contacts

Contact: Stephen Helmke; 212-932-4537; sh2669@cumc.columbia.edu

Contact: Mathew S. Maurer, MD; 212-305-9808; msm10@cumc.columbia.edu

Locations

United States, Massachusetts

Boston Medical Center; Recruiting

Boston, Massachusetts, United States, 02118

Contact: Denise Fine 617-638-8716

Principal Investigator: Frederick L. Ruberg, MD

United States, New York

Allen Hospital; Recruiting

New York, New York, United States, 10032

Contact: Stephen Helmke, RDCS MPH 212-932-4537 sh2669@cumc.columbia.edu

Principal Investigator: Mathew S. Maurer, MD

Harlem Hospital; Recruiting

New York, New York, United States, 10037

Contact: Damian C. Kurian, MD 212-939-4701 damian.kurian@nychhc.org

Contact: Ivrose Janvier, PA 212-939-4700 Ivrose.Janvier@nychcc.org

Principal Investigator: Damian C. Kurian, MD

Sponsors and Collaborators

Mathew Maurer

National Heart, Lung, and Blood Institute (NHLBI)

Boston Medical Center

Harlem Hospital Center

The Scripps Research Institute

Investigators

• Principal Investigator: Mathew S. Maurer, MD; Columbia University
• Principal Investigator: Frederick L Ruberg, MD; Boston Medical Center/Boston University Medical Center

More Information

Publications:

Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27.

Maurer MS, Ruberg FL, Weinsaft JW. More Than Meets the Eye: Time for a New Imaging Paradigm to Test for Cardiac Amyloidosis. J Card Fail. 2018 Feb;24(2):87-89. doi: 10.1016/j.cardfail.2017.12.006. Epub 2018 Jan 3.

Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, Pozniakoff T, Ruberg FL, Miller EJ, Berk JL, Dispenzieri A, Grogan M, Johnson G, Bokhari S, Maurer MS. Multicenter Study of Planar Technetium 99m Pyrophosphate Cardiac Imaging: Predicting Survival for Patients With ATTR Cardiac Amyloidosis. JAMA Cardiol. 2016 Nov 1;1(8):880-889. doi: 10.1001/jamacardio.2016.2839.

Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12. doi: 10.1161/CIRCULATIONAHA.116.021612. Epub 2016 Apr 22.

Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, Falk RH, Cheung KN, Patel AR, Pano A, Packman J, Grogan DR. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012 Aug;164(2):222-228.e1. doi: 10.1016/j.ahj.2012.04.015.

Ruberg FL, Judge DP, Maurer MS. Familial amyloid cardiomyopathy due to TTR mutations: an underdiagnosed cause of restrictive cardiomyopathy [corrected]. J Card Fail. 2009 Jun;15(5):464. doi: 10.1016/j.cardfail.2009.04.003. Erratum in: J Card Fail. 2009 Aug;15(6):552.

• Responsible Party: Mathew Maurer, Arnold and Arlene Goldstein Professor of Cardiology, Columbia University
• ClinicalTrials.gov Identifier: NCT03812172
• Other Study ID Numbers: AAAS4054; R01HL139671-01A1 ( U.S. NIH Grant/Contract )
• First Posted: January 23, 2019
• Last Update Posted: July 26, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Mathew Maurer, Columbia University:

Heart Failure; Cardiac Amyloidosis; TTR mutation; Blacks; Hispanics; Aging

Additional relevant MeSH terms:

Cardiomyopathies; Amyloidosis; Heart Diseases; Cardiovascular Diseases; Proteostasis Deficiencies; Metabolic Diseases