DCM Precision Medicine Study

Idiopathic Dilated Cardiomyopathy Clinical Trial

Official title:

Precision Medicine for Dilated Cardiomyopathy in European and African Ancestry

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03037632
• Other study ID #: 2015H0309
• Secondary ID: R01HL128857
• Status: Active, not recruiting
• Phase: N/A
• Start date: June 7, 2016
• Est. completion date: April 30, 2024

Study information

• Verified date: March 2024
• Source: Ohio State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aims of the DCM Precision Medicine Study are to test the hypothesis that DCM has substantial genetic basis and to evaluate the effectiveness of a family communication intervention in improving the uptake and impact of family member clinical screening.

Description:

Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomypathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. The central hypothesis of this study, based on published studies of the investigative group, states that DCM has substantial genetic basis. For this study the investigators hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, the investigators propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM. These aims will be accomplished by recruiting a cohort of 1300 DCM probands (600 EA, 600 AA, 100 Hispanic ethnicity), performing cardiovascular clinical screening of 2600 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, cardiovascular professionals would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. These study results would make precision medicine for DCM a reality.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6500
• Est. completion date: April 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Meeting criteria for dilated cardiomyopathy (DCM) :
• Left ventricular ejection fraction <50%
• Left ventricular enlargement (A left ventricular end-diastolic dimension > 95%tile population standard based on gender and height).
• Detectable causes of cardiomyopathy, except genetic, excluded beyond a reasonable doubt at the time of DCM diagnosis (that is, meeting clinical criteria for idiopathic DCM)
• Any age (including children)
• Non-Hispanic and Hispanic ethnicity
• All races (PI pre-approval required for recruitment beyond pre-specified recruitment targets).
• Ability to give informed consent
• Ability to communicate in English (except Spanish language at sites approved to recruit individuals of Hispanic ethnicity)
• Willingness to participate in a family-based study (patient willing to work with a clinical site and/or OSU to facilitate the recruitment and enrollment of family members to the study).

Exclusion Criteria:

• Coronary artery disease (CAD) causing ischemic cardiomyopathy (> 50% narrowing, any major epicardial coronary artery)
• Primary valvular disease
• Adriamycin or other cardiotoxic drug exposure
• Other forms of cardiomyopathy: Hypertrophic, Restrictive, or Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
• Congenital heart disease
• Other detectable causes of dilated cardiomyopathy, including sarcoid and hemochromatosis.
• Other active multi-system disease that may cause DCM (e.g., active connective tissue disease).
• Severe and untreated or untreatable hypertension (systolic blood pressures routinely greater than 180 mm Hg and/or diastolic blood pressures greater than 120 mm Hg, and if resistant to multidrug treatment).
• However, conventional risk factors for DCM, including obesity, routinely treated hypertension, alcohol use, pregnancy or the peri-partum period, or left ventricular noncompaction, will NOT be considered exclusion criteria.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Idiopathic Dilated Cardiomyopathy

Intervention

Behavioral:
• Family Heart Talk Booklet

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Cedars-Sinai Medical Center	Beverly Hills	California
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Tufts Medical Center	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Inova Heart and Vascular Institute	Fairfax	Virginia
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	UCLA Medical Center	Los Angeles	California
United States	South Miami Heart Center	Miami	Florida
United States	Louisiana State University Health Sciences Center in New Orleans	New Orleans	Louisiana
United States	NYU School of Medicine	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of Washington	Seattle	Washington
United States	University of Arizona Sarver Heart Center	Tucson	Arizona
United States	Medstar Washington Hospital Center (DC)	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Ray Hershberger	National Heart, Lung, and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI)

Country where clinical trial is conducted

United States, 

References & Publications (12)

Burke W, Hovick SR, Jordan E, Ni H, Kinnamon DD, Hershberger RE. Communal Coping as a Strategy to Enhance Family Engagement in Dilated Cardiomyopathy. Circ Genom Precis Med. 2022 Jun;15(3):e003541. doi: 10.1161/CIRCGEN.121.003541. Epub 2022 May 10. — View Citation

Haas GJ, Zareba KM, Ni H, Bello-Pardo E, Huggins GS, Hershberger RE; Study Principal Investigator (PI) and Co-Investigators: The Ohio State University. Validating an Idiopathic Dilated Cardiomyopathy Diagnosis Using Cardiovascular Magnetic Resonance: The Dilated Cardiomyopathy Precision Medicine Study. Circ Heart Fail. 2022 May;15(5):e008877. doi: 10.1161/CIRCHEARTFAILURE.121.008877. Epub 2022 Mar 4. — View Citation

Hershberger RE, Cowan J, Jordan E, Kinnamon DD. The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy. Circ Res. 2021 May 14;128(10):1514-1532. doi: 10.1161/CIRCRESAHA.121.318157. Epub 2021 May 13. — View Citation

Hershberger RE. The Evolving Science of Dilated Cardiomyopathy. J Am Coll Cardiol. 2021 Oct 26;78(17):1700-1702. doi: 10.1016/j.jacc.2021.08.038. No abstract available. — View Citation

Huggins GS, Kinnamon DD, Haas GJ, Jordan E, Hofmeyer M, Kransdorf E, Ewald GA, Morris AA, Owens A, Lowes B, Stoller D, Tang WHW, Garg S, Trachtenberg BH, Shah P, Pamboukian SV, Sweitzer NK, Wheeler MT, Wilcox JE, Katz S, Pan S, Jimenez J, Aaronson KD, Fishbein DP, Smart F, Wang J, Gottlieb SS, Judge DP, Moore CK, Mead JO, Ni H, Burke W, Hershberger RE; DCM Precision Medicine Study of the DCM Consortium. Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy. JAMA. 2022 Feb 1;327(5):454-463. doi: 10.1001/jama.2021.24674. — View Citation

Jordan E, Kinnamon DD, Haas GJ, Hofmeyer M, Kransdorf E, Ewald GA, Morris AA, Owens A, Lowes B, Stoller D, Tang WHW, Garg S, Trachtenberg BH, Shah P, Pamboukian SV, Sweitzer NK, Wheeler MT, Wilcox JE, Katz S, Pan S, Jimenez J, Fishbein DP, Smart F, Wang J, Gottlieb SS, Judge DP, Moore CK, Mead JO, Hurst N, Cao J, Huggins GS, Cowan J, Ni H, Rehm HL, Jarvik GP, Vatta M, Burke W, Hershberger RE; DCM Precision Medicine Study of the DCM Consortium. Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry. JAMA. 2023 Aug 1;330(5):432-441. doi: 10.1001/jama.2023.11970. — View Citation

Kinnamon DD, Jordan E, Haas GJ, Hofmeyer M, Kransdorf E, Ewald GA, Morris AA, Owens A, Lowes B, Stoller D, Tang WHW, Garg S, Trachtenberg BH, Shah P, Pamboukian SV, Sweitzer NK, Wheeler MT, Wilcox JE, Katz S, Pan S, Jimenez J, Aaronson KD, Fishbein DP, Smart F, Wang J, Gottlieb SS, Judge DP, Moore CK, Mead JO, Huggins GS, Ni H, Burke W, Hershberger RE; DCM Precision Medicine Study of the DCM Consortium. Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial. Circulation. 2023 Apr 25;147(17):1281-1290. doi: 10.1161/CIRCULATIONAHA.122.062507. Epub 2023 Mar 20. — View Citation

Kinnamon DD, Morales A, Bowen DJ, Burke W, Hershberger RE; DCM Consortium*. Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study. Circ Cardiovasc Genet. 2017 Dec;10(6):e001826. doi: 10.1161/CIRCGENETICS.117.001826. — View Citation

Morales A, Kinnamon DD, Jordan E, Platt J, Vatta M, Dorschner MO, Starkey CA, Mead JO, Ai T, Burke W, Gastier-Foster J, Jarvik GP, Rehm HL, Nickerson DA, Hershberger RE; DCM Precision Medicine study of the DCM Consortium; DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators,DCM Consortium Clinical Site Principal Investigators and Clinical Site Other Significant Contributors (OSC). The following clinical sites and individuals contributed to the submission of RO 1 H L 128857 as Site Principal Investigators (Site Pl) or as Other Significant Contributors (OSC),Dr. Huggins also served as study co-principal investigator,The following clinical site was added following approval of NHGRI supplemental funding but prior to initiation of enrollment,The following clinical sites were added following study activation. Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. Circ Genom Precis Med. 2020 Apr;13(2):e002480. doi: 10.1161/CIRCGEN.119.002480. Epub 2020 Mar 11. — View Citation

Ni H, Jordan E, Cao J, Kinnamon DD, Gottlieb SS, Hofmeyer M, Jimenez J, Judge DP, Kransdorf E, Morris AA, Owens A, Shah P, Tang WHW, Wang J, Hershberger RE. Knowledge of Genome Sequencing and Trust in Medical Researchers Among Patients of Different Racial and Ethnic Groups With Idiopathic Dilated Cardiomyopathy. JAMA Cardiol. 2023 Jan 1;8(1):33-42. doi: 10.1001/jamacardio.2022.4132. — View Citation

Ni H, Jordan E, Kinnamon DD, Cao J, Haas GJ, Hofmeyer M, Kransdorf E, Ewald GA, Morris AA, Owens A, Lowes B, Stoller D, Tang WHW, Garg S, Trachtenberg BH, Shah P, Pamboukian SV, Sweitzer NK, Wheeler MT, Wilcox JE, Katz S, Pan S, Jimenez J, Fishbein DP, Smart F, Wang J, Gottlieb SS, Judge DP, Moore CK, Huggins GS, Hershberger RE; DCM Precision Medicine Study of the DCM Consortium. Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives. J Am Coll Cardiol. 2023 May 30;81(21):2059-2071. doi: 10.1016/j.jacc.2023.03.419. — View Citation

Trachtenberg BH, Jimenez J, Morris AA, Kransdorf E, Owens A, Fishbein DP, Jordan E, Kinnamon DD, Mead JO, Huggins GS, Hershberger RE; DCM Precision Medicine Study of the DCM Consortium. TTR variants in patients with dilated cardiomyopathy: An investigation of the DCM Precision Medicine Study. Genet Med. 2022 Jul;24(7):1495-1502. doi: 10.1016/j.gim.2022.03.011. Epub 2022 Apr 18. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Family clinical screening completed within 12 months from proband enrollment.	The probability that a living first-degree relative (FDR) without a previous definitive DCM diagnosis completes clinical screening for DCM within 12 months after proband recruitment	12 months from proband enrollment.
Primary	Living first-degree relative adheres to cardiovascular surveillance recommendations after return of genetic results.	The probability that a living first-degree relative adheres to surveillance recommendations within 15 months after the proband receives individual genetic test information.	2.5 years

External Links

•   Additional information regarding DCM Precision Medicine Study information provided on website.